MXPA06006034A - Multiparticulate compositions with improved stability - Google Patents

Abstract

A process is described for producing drug-containing multiparticulates with improved stability, characterized by an improvement in one or more of chemical stability, physical stability, or dissolution stability.

Description

MULTIPARTICULATED COMPOSITIONS WITH IMPROVED STABILITY BACKGROUND OF THE INVENTION Multiparticulates are notorious pharmaceutical forms comprising a multiplicity of particles whose totality represents the therapeutically useful dose intended for a drug. When ingested orally, multiparticulates generally disperse freely in the gastrointestinal tract, maximize absorption, and minimize side effects. See for example: Multiparticulate Oral Drug Delivery (Marcel Dekker, 1994), and Pharmaceutical Pelletization Technology (Marcel Dekker, 1989). It is well known that some drugs can exist in several different crystalline forms. A specific example of a drug that can exist in one of several crystalline forms is azithromycin, for which many different crystalline forms have been identified to date. See United States patent application publication in commonly owned with this n ° 20030162730. The most stable form of azithromycin at ambient temperature and humidity (eg, 25 ° C and 50% relative humidity) is the dihydrate crystalline which is described in U.S. Patent No. 6,268,489, which is a crystalline form that includes water. It is known that some multiparticulate formulations of drugs, especially those that use a vehicle with lipid base or glycerides, show changes in the behavior at maturity under controlled conditions. See, for example, San Vicente et al., 208 Intl. J. Pharm. 13 (2000), U.S. Patent No. 5,213,810, Jorgensen et al., 153 Intl. J. Pharm. 1 (1997), Eldem et al., 8 Pharm.

Res. 47 (1991) and Eldem et al., 8 Pharm. Res. 178 (1991). The changes that are observed in e! Behaviors are often attributed to changes in vehicle morphology over time, but there is no description or suggestion of any procedure to prevent such changes in morphology. The product literature provided by Gattefossé, manufacturers of Gelucire® products (blends of fatty acid esters of glycerol and polyethylene glycol) suggest the heat treatment of Gelucire®-based drug formulations that are filled into hard gelatin capsules. Gelucire® Technical Dossier (2nd Ed 1996). However, the use of such a procedure for the stabilization of multiparticulates is not described. The Bulletin Technique Gattefossé No. 89, page 47, (1996) describes that the release of drugs from formulations containing Gelucire® bases can change with storage, but grants that very little is known about how to prevent such changes U.S. Patent Nos. 5,597,416, 5,869,098, 6,048,541 and 6,165,512 all describe a process for crystallizing sugars in amorphous raw materials by exposing the raw material to a crystallization enhancer, such as ethanol. However, there is no suggestion of the use of such a procedure to stabilize a multiparticulate containing drugs. Thus, there is a need in the art for methods for forming multiparticulates containing drugs that have improved stability. This invention addresses that need. BRIEF SUMMARY OF THE INVENTION The inventors have discovered that the drawbacks outlined above can be solved by treating such multiparticulates with controlled heat and / or with an agent that enhances mobility upon formation, which results in an increase in the crystallinity of the drug, and in some embodiments, better chemical stability, physical stability, and / or dissolution stability. In a first aspect, the invention provides a method for producing multiparticulates comprising the steps of (a) forming multiparticulates comprising a drug and a pharmaceutically acceptable carrier, wherein the carrier has a melting point of Tm ° C; and (b) subsequently treating the multiparticulates by at least one of (i) heating them to a temperature of at least about 35 ° C and less than about (Tm ° C-10 ° C), or (i) exposing them to an agent that promotes mobility, in which the subsequent treatment is carried out for a sufficient period of time to achieve a crystallinity of the drug in the multiparticulates that is greater than the crystallinity of the drug in a control composition of the multiparticulates of stage (a). In a second aspect, the invention provides pharmaceutical compositions comprising multiparticulates containing drugs prepared by the process of the invention. In a third aspect, the invention also provides a method for treating a patient in need of drug treatment by administering to the patient a therapeutically effective amount of a pharmaceutical composition of the invention. DETAILED DESCRIPTION OF THE INVENTION A main objective of the present invention is to provide multiparticulate drug compositions with high crystallinity of the drug and optimally, with improved stability, characterized by any or all of improved chemical stability, improved physical stability or improved dissolution stability. . The term "multiparticulate" is intended to encompass a pharmaceutical form comprising a multiplicity of particles whose totality represents the intended therapeutically useful dose of the drug. The particles generally have a mean diameter of from about 40 to about 3000 μm, preferably from about 50 to 1000 μm, and most preferably from about 100 to about 300 μm. Although a multiparticulate can have any shape and texture, it is usually spherical with a smooth surface. As used in the present invention, the term "approximately" means the specified value ± 10% of the specified value. The term "vehicle" is defined as a pharmaceutically acceptable material that is used primarily as a matrix or to control the rate of release of the drug, or both. The vehicle can be a single material or a mixture of two or more materials. The phrase "aqueous use environment" as used herein, refers either to fluids in vivo or to an in vitro experimentation medium. "Introduction" in an environment of use includes either ingestion when the environment of use is in vivo, or placement in a medium of experimentation when the environment of use is in vitro. The term "patient" encompasses all animals, particularly mammals, and especially humans, although any animal that may benefit from the use of a drug is considered to be within the scope of the invention.

Subsequent treatment of multiparticulates As mentioned in the Background, some multiparticulate pharmaceutical forms show changes in behavior at maturity. Without wishing to be bound by any particular theory or mechanism of action, it is believed that when the multiparticulates are prepared by various procedures, they are initially in a thermodynamically unstable form, which means that the drug and the vehicle used in the composition initially do not they are in their lowest energetic state. As a result, the physical state of the materials changes as they go back to a lower energy state over time. This return to a lower energy state is often characterized by changes in the physical nature, chemical stability, or dissolution behavior of the multiparticulate. For example, the solubility of a drug in a vehicle is a function of temperature, physical state (for example, amorphous or crystalline and, if crystalline, the crystalline form), and the moisture content or solvent of the vehicle. Often, the solubility increases with increasing temperature. In some multiparticulate forming processes, the drug and the vehicle are exposed to temperatures that are higher than typical storage temperatures (eg, up to 40 ° C) for multiparticulates. As a result, the solubility of the drug in the vehicle during the manufacturing process of the multiparticulate is greater than its solubility under storage conditions. During the process of forming the multiparticulates, a portion of the crystalline drug will dissolve in the molten vehicle up to the solubility limit of the drug in the molten vehicle under the processing conditions. When the molten vehicle is initially cooled to form the multiparticulates, the multiparticulate will consist of particles of crystalline drug substance encapsulated in a solid vehicle solution and the dissolved drug. Upon further cooling, the solubility of the drug in the vehicle will decrease, producing a crystalline drug encapsulated in a supersaturated solid solution of non-crystalline drug in the vehicle. Over time, the concentration of non-crystalline drug in this supersaturated solid solution will decrease until the drug reaches its limit solubility in the vehicle. The non-crystalline drug above this solubility limit will form drug-rich regions in the multiparticulate (i.e., the phases of the solid solution will separate). The multiparticulate thus consists of crystalline drug encapsulated in vehicle, and non-crystalline drug in regions rich in drug. The drug from these drug-rich regions may remain in a non-crystalline state (ie, amorphous) or in some cases, may crystallize over time, producing additional changes in the physical state of all or a portion of the drug over time. This change in the drug status in the vehicle can also produce changes in the rate of dissolution of the drug in the multiparticulates. In addition, the drug in a non-crystalline state is often more susceptible to chemical degradation than the crystalline drug; as a result, the multiparticulate drug may have a decreased chemical stability. Other multiparticulate manufacturing processes use liquids or solvents in which the drug is very soluble. In such procedures, a portion of the drug in the liquid is dissolved during the manufacturing process of the multiparticulate. When the liquid is then removed from the multiparticulate, the drug can precipitate, for example, in the form of an amorphous solid. As indicated above, this can produce physical instability, chemical instability, or dissolution instability of the drug in the multiparticulate. In addition, it is also notorious that some vehicles, especially fats such as glyceryl esters, when they freeze rapidly in the molten state, they may be present, at least partially in an amorphous state or in a crystalline state other than their more stable crystalline state, such high energy crystalline states are called unstable polymorphs. Over time, the physical state of the fat may vary, generally becoming the stable polymorph. Such changes in the physical state of the vehicle can produce an instability of the drug in the multiparticulate with time. Specifically, the drug is generally less soluble in crystalline fat than in an amorphous fat and thus, upon crystallizing the fat, any dissolved drug can be separated into a drug-rich crystalline or amorphous phase. Likewise, when the multiparticulates comprise a vehicle and one or more optional excipients, the solubility of the optional excipient in the vehicle during the manufacturing process of the multiparticulate may be greater than its solubility under typical storage conditions. As indicated above in the case of the solubility of the drug in the vehicle, over time, the optional excipient can be separated into excipient-rich regions that are rich in the excipient, and vehicle-rich regions that are rich in the vehicle. . Such changes in the physical state of the components of the multiparticulate can produce a multiparticulate instability. Other changes in multiparticulates may occur over time, due in part to the relaxation of the drug or vehicle to a lower energy state, which includes changes in porosity, pore interconnection, and the size and number of empty spaces. in the multiparticulate. These changes can also produce changes in the dissolution behavior of the multiparticulate over time. In each of these cases, changes in the physical state of the drug or vehicle present in the multiparticulates can produce a physical, chemical or dissolution instability in the multiparticulates. The inventors have discovered that the stability of the multiparticulates can be improved by using the post-treatment process described herein. Generally, the conditions of the subsequent treatment will be determined in such a way that the drug and the vehicle substantially revert to their lower energy states. This is achieved by exposing the multiparticulate at elevated temperatures, exposing it to an agent that enhances mobility, or both. As described above, the lowest energy state of the drug will normally be a crystalline state. Thus, preferably, the post-treatment conditions are chosen in such a way that any amorphous drug or drug dissolved in the formed vehicle is substantially converted back to a crystalline state. Preferably, the crystalline state is the same crystalline state in which the drug was before the formation of the multiparticulate. In one aspect, the multiparticulates are subjected to further treatment by exposure to elevated temperatures. The inventors have discovered that the higher the temperature of the subsequent treatment, the faster the drug and / or vehicle revert to their lower energy states. Thus, the subsequent treatment process is preferably carried out at a temperature of at least about 35 ° C, more preferably at least about 40 ° C. However, if the temperature of the subsequent treatment is too high, damage to the multiparticulates may occur, or they may agglomerate during the subsequent treatment process, altering their dissolution behavior. Thus, the subsequent treatment procedure should be carried out at a temperature of less than about (Tm-10 ° C), where Tm is the melting point of the vehicle in ° C. As used herein, "vehicle melting point" means the temperature at which the vehicle, when it contains the drug and any optional excipients present in the multiparticulate, it goes from its crystalline state to its liquid state. When the vehicle is not crystalline, "melting point of the vehicle" means the temperature at which the vehicle becomes fluid in the sense that it will flow when subjected to one or more forces such as pressure, cut and centrifugal force, of a shape similar to a crystalline material in liquid state. The inventors have found that when the subsequent treatment process is performed below this temperature, the multiparticulates are not damaged and agglomeration is minimized. Such subsequent treatment can be carried out in any apparatus that controls the temperature of the multiparticulates. Examples of such apparatuses are well known in the art, and include tray dryers, ovens, fluid beds, double shell mixers, extruders such as single screw and twin screw extruders and V mixers. Multiparticulates can be introduced into an apparatus of that type. type while being exposed to the ambient atmosphere, or may be exposed to a controlled atmosphere such as an atmosphere containing an agent that enhances mobility, as described below. Alternatively, the multiparticulates can be sealed in a container, such as a bottle, box, drum, bag or bag and then introduced into the apparatus at a controlled temperature.

In a separate aspect, multiparticulates can also be subjected to subsequent treatment simply by exposure to an agent that enhances mobility. The agent that enhances mobility increases the mobility of the drug in the multiparticulate, allowing the drug and / or the vehicle to form more rapidly in lower energy states. By "mobility" is meant the movement or diffusion of the drug and / or vehicle in the multiparticulate. The agent that promotes mobility achieves it by being absorbed at least partially in the multiparticulate. Suitable agents that enhance mobility include water, methanol, ethanol, propanol and its isomers, butanol and its isomers, acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl acetate, tetrahydrofuran, acetonitrile, cyclohexane, formic acid, acetic acid, and mixtures thereof. The mobility enhancing agent may be present in the form of a liquid, a vapor, or a mixture of a liquid and vapor during the post-treatment process. For example, the post-treatment process can be carried out by spraying the mobility enhancing agent in liquid form over the multiparticulates in a suitable container, such as a double shell mixer. Alternatively, the multiparticulates may be contacted with a jet of gas containing the mobility enhancing agent, such as in a fluid bed apparatus. In any case, the agent that enhances mobility should be added to the multiparticulates in such a way that the concentration of the agent that promotes mobility is substantially uniform in all the multiparticulates that are being treated. The amount of agent that enhances the mobility necessary to perform a subsequent treatment of the multiparticulates will depend on the agent that promotes the mobility that is used and the characteristics of the drug, the vehicle, and other optional excipients of the multiparticulate. After exposure, the agent that enhances mobility is absorbed by the multiparticulates. Thus, a sufficient amount of agent that enhances mobility should be used to increase the mobility of the drug and / or vehicle so that they can rapidly revert substantially to their lower energy states. When the mobility enhancing agent is added in the vapor phase, the amount of gas containing the mobility enhancing agent must be large enough that a sufficient amount of agent is absorbed by the multiparticulates. In addition, the gas containing the agent must be contacted with the multiparticulates in a manner and for a sufficient time so that the vapor is suitably absorbed by the multiparticulates. A procedure for determining the amount of agent that enhances the mobility necessary for the subsequent treatment of the multiparticulates is as follows. A sample of the multiparticulates and an amount of the mobility promoting agent are sealed in a container, such as a flask or vial. The amount of agent that enhances mobility is such that if all the mobility enhancing agent evaporated in the package volume would be approximately 50% of the saturation vapor pressure of the agent that enhances mobility under the conditions of the test. Then, periodically, samples are taken from the multiparticulates in the container and analyzed to determine the crystallinity of the drug by PXRD (diffraction of fine crystals by X-rays) or some other quantitative procedure. This test is then repeated by introducing other amounts of agent that enhances mobility in the vessel, such as about 75% of the saturation vapor pressure and about 95% of the saturation vapor pressure. An amount of agent that enhances mobility greater than 100% of the saturation vapor pressure can also be used. From these data, the relationship between the amount of agent that enhances the mobility necessary to perform a subsequent treatment of the multiparticulates and the time during which to perform the subsequent treatment of the multiparticulates can be determined. Once the post-treatment procedure has been completed, a portion of the agent that enhances the mobility of the multiparticulate is often eliminated. In some cases, a portion of the agent that enhances the mobility of the multiparticulate during the post-treatment process is removed, such as by evaporation, pan drying, vacuum drying, and other methods known in the art. See for example, Remington: The Science and Practice of Pharmacy, 20th Edition (2000). An especially preferred form of treatment is to expose the multiparticulates to the agent that promotes mobility in a vaporized state. For example, when the mobility promoting agent is water, the multiparticulates may be exposed to a gas phase atmosphere, such as nitrogen or air having a relative humidity (RH) of greater than about 10%, more preferably greater than about 30% , and most preferably greater than about 50%. In another aspect, the post-treatment process can also be performed by exposing the multiparticulates to an agent that promotes mobility at elevated temperatures. In such cases, the multiparticulates may first be exposed to the mobility enhancing agent as described above, and then exposed to elevated temperatures using the apparatus and methods described above. Alternatively, the multiparticulates may be exposed to the agent that promotes mobility at an elevated temperature. For example, the multiparticulates may be introduced into a suitable container, such as a fluid bed provided with a hot fluidization gas and the mobility enhancing agent sprayed onto the multiparticulates. Alternatively, a hot gas containing the agent that enhances mobility in the fluid bed containing the multiparticulates can be introduced. When such post-treatment processes are performed, it is preferred that the mobility promoting agent be absorbed by the multiparticulates at the processing temperature. Further, it is preferred that the post-treatment process be carried out at a temperature of at least about 35 ° C, preferably at least about 40 ° C, and less than about (Tm-10 ° C). A person skilled in the art will realize that the value of Tm can be affected by the amount of agent that enhances the mobility present in the multiparticulates and the subsequent treatment temperature should therefore be chosen accordingly. The post-treatment time should be broad enough to allow the crystallinity of the drug of the multiparticulates to increase and / or to reach a sufficiently stable low energy state, but at the same time not so broad that it is impractical from the point of view of commercial manufacturing Generally, it is preferred that the subsequent treatment time be about 8 weeks or less, preferably about 6 weeks or less, and most preferably about 4 weeks or less. The subsequent treatment time necessary to achieve a stable composition will vary depending on the temperature of the subsequent treatment, shorter times being necessary at higher temperatures and longer times at lower temperatures being necessary. A particularly effective subsequent quenching comprises exposing the multiparticulates at a temperature between about 40 ° C and about 50 ° C, and at an air atmosphere with a water content in the vapor phase between about 50% RH and 100% RH during a time from about 1 to about 30 days, preferably from about 5 to about 20 days, and most preferably about 10 days. Such subsequent treatment can be carried out in any apparatus that allows the multiparticulates to be in contact with the humid air in such a way that there is a controlled temperature and humidity. Examples of such apparatuses include tray dryers, environmental furnaces, fluid beds, double shell mixers, twin screw extruders and V mixers. Due to variations in the uniformity of temperature and humidity in such appliances, you must ensure that the subsequent treatment conditions that are selected produce multiparticulates stable in the selected device. For example, tests should be performed to ensure that the depth of the bed depth in a tray dryer used for the subsequent processing of the multiparticulates is not so high that the multiparticulates in the bottom of the bed do not absorb the necessary level of agent. it enhances mobility, such as water, in a sufficiently rapid time in such a way that the subsequent treatment in them is not carried out adequately to stabilize the speed of drug release of the multiparticulates. In another aspect, the subsequent treatment of the multiparticulates can be done by mixing the agent that promotes mobility with the multiparticulates and then sealing the agent that promotes mobility and the multiparticulates; in a container so as to ensure the retention of the agent that enhances mobility in the multiparticulates, optionally followed by heating the container to the desired post treatment temperature. Examples of suitable containers include bags, drums, jars, sacks and boxes. The sealed container containing the multiparticulates and the mobility enhancing agent can then be introduced into a hot room or oven which is maintained at the desired post-treatment temperature. In yet another aspect, the agent that enhances mobility can be incorporated into the multiparticulates during the multiparticulate formation process, so that the mobility enhancing agent is present in the multiparticulates after formation. To optionally carry out the subsequent treatment by heating, the multiparticulates containing the mobility enhancing agent can be sealed in a container and then introduced into a temperature controlled environment, as described above. Specific procedures for incorporating an agent that enhances mobility to multiparticulates during the training process are described in greater detail below. The post-treatment process is carried out for a sufficient time so that the crystallinity of the multiparticulate drug increases compared to a multiparticulate control consisting essentially of the untreated multiparticulate. By "multiparticulate untreated" is meant a multiparticulate that has not been treated by heating and / or exposure to an agent that enhances mobility or has been stored for a prolonged period of time after multiparticulate formation. A person skilled in the art will recognize that it is inevitable that some storage time passes between the formation of the multiparticulate and the evaluation of the multiparticulate; however, this time should be minimized when selected for a multiparticulate control. By "crystallinity" is meant the fraction of drug in a crystalline state as opposed to a non-crystalline or amorphous state. Generally, the crystallinity of the drug in the multiparticulates increases with time during the subsequent treatment procedure. The post-treatment process of the present invention produces an increase in the crystallinity of the drug in the multiparticulate compared to the multiparticulate control described above. At a minimum, the post-treatment procedure produces an increase in the crystallinity of the drug that is within the accuracy of the procedure that is used to determine the crystallinity of the drug in the composition. For example, if the crystallinity of the drug in a multiparticulate is measured as 90 ± 4% by weight, then the multiparticulate subjected to further treatment by the process of the present invention will have a crystallinity greater than 94% by weight when measured using the same instrument or methodology. The crystallinity of the drug in a multiparticulate can be determined using X-ray fine crystal diffraction analysis (PXRD). In an exemplary procedure, analysis by PXRD can be performed on a Bruker AXS D8 Advance diffractometer. In this procedure, samples of multiparticulates weighing approximately 500 mg are introduced into Lucite sample vessels and the surface of the sample is smoothed using a glass microscope slide providing a consistently smooth sample surface that is flush with the top of the sample glass. The samples are centrifuged in a plane f at a speed of 30 rpm to minimize the orientation effects of the crystals. The X-ray source (S / B KCu_,? = 1.54 Á) is operated at a voltage of 45 kV and a current of 40 mA. The data for each sample is collected over a period of approximately 20 to 60 minutes in continuous detection scan mode with a scanning speed of approximately 1 to 15 seconds / step and a step size of 0, 02 step. The diffractograms are collected in the 2T interval from 4o to 30 °. The crystallinity of the experimental sample is determined by comparing with two or more calibration standards consisting of physical mixtures of crystalline drug and vehicle. Each physical mix is mixed 15 minutes in a Turbula mixer. Using the instrument software, the area under the curve of the diffractogram is integrated in the 2T interval using a linear initial level. This integration interval includes as many specific peaks of the drug as possible while excluding peaks related to the excipients. A linear calibration curve of percentage of crystalline drug is generated as a function of the area under the curve of the diffractogram from the calibration standards. The crystallinity of the experimental sample is then determined using these calibration results and the area under the curve for the experimental sample. The results are expressed in terms of average percent crystallinity of the drug per mass of the crystals. In one aspect, the multiparticulates are subjected to further treatment for a sufficient time to achieve a degree of drug crystallinity of at least 95%. Preferably, at least 95% of the drug in the multiparticulate subjected to further treatment is in the same crystalline state as the drug was before the formation of the multiparticulates. A useful way to quantify an increase in the crystallinity of the drug in a multiparticulate is to determine the relative degree of improvement of the crystallinity of the drug in the multiparticulate, which means the ratio between (1) the amount of non-crystalline drug in a multiparticulate of control and (2) the amount of non-crystalline drug in a multiparticulate subjected to further treatment. (The amount of non-crystalline drug can be taken as 100% by weight minus the amount of crystalline drug in the multiparticulate.) For example, if the amount of crystalline drug in the multiparticulate control is 80% by weight, and the amount of crystalline drug in the multiparticulate subjected to further treatment is 90% by weight, the relative degree of improvement of the crystallinity is (100% by weight - 80% by weight) / (100% by weight - 90% by weight) = 20% by weight / 10% by weight = 2.0. In one embodiment, the post-treatment process is carried out for a time sufficient for the multiparticulate to have a relative degree of crystallinity improvement of at least 1.1, preferably at least 1.25, more preferably at least 1, 5 and even more preferably at least 2.0. Procedures for forming multiparticulates Multiparticulates can be prepared by any process that produces multiparticulate formation containing drugs. As mentioned above, the particles generally have an average diameter of from about 40 to about 3000 μm, although more typically the diameter ranges from about 50 to about 1000 μm. Although a multiparticulate can have any shape and texture, it is usually spherical with a smooth surface. Preferred methods for forming the multiparticulates include thermally based processes such as melt-freezing and spray-freezing, liquid-based processes, such as extrusion / spheronization, wet granulation, spray coating, spray drying and other granulation processes such such as dry granulation and melt granulation. In one aspect, the multiparticulates are produced by a melt-freezing process comprising the steps of (a) forming a molten mixture comprising a drug and a pharmaceutically acceptable carrier, (b) administering the molten mixture from the stage (a) ) to an atomizing medium forming droplets of the molten mixture, and (c) freezing the droplets of step (b) to form multiparticulates. The melt-freezing process is more fully described in commonly assigned U.S. patent applications with the present serial number 60/527244 ("Improved Azithromycin Multiparticulate Dosage Forms by Melt-Congeal Processes., "No. of record PC250Í5), and 60/527315 (" Extrusion Process for Forming Chemically Stable Drug Multiparticulates, "No. of record PC25122), filed December 4, 2003. The melt mixture may comprise (1) drug dissolved in the molten vehicle, (2) drug suspended in the molten vehicle, (3) vehicle suspended in the molten drug, (4) molten drug suspended in the molten vehicle, or (5) any combination of such states or those states in between In a preferred embodiment, the molten mixture comprises substantially crystalline drug particles substantially uniformly suspended in a vehicle that is substantially fluid In such cases, a portion of the drug can be dissolved in the fluid vehicle and a portion of the vehicle can remain preferably, less than about 30% by weight of the total drug is melted or dissolved in the molten vehicle. It is meant that the mixture of drug and vehicle is sufficiently heated so that the mixture becomes sufficiently fluid so that the mixture can be formed into droplets or atomized. The atomization of the molten mixture can be carried out using any of the spray methods described below. Generally, the mixture is melted in the sense that it will flow when subjected to one or more forces such as pressure, cut and centrifugal force, such as that exerted by a centrifugal or rotating disk atomizer. Thus, the mixture of drug and vehicle can be considered "molten" when the mixture becomes sufficiently fluid so that it can be atomized. Generally, a mixture is sufficiently fluid to be atomized when the viscosity of the molten mixture is less than about 20,000 mPa-s, preferably less than about 15,000 mPa-s, more preferably less than about 10,000 mPa-s. Often, the mixture becomes molten when the mixture is heated above the melting point of one or more of the vehicle components, in cases where the vehicle is sufficiently crystalline to have a relatively high melting point.; or when the vehicle components are amorphous, above the softening point of one or more of the vehicle components. Thus, the molten mixture is often a suspension of solid particles in a fluid matrix. In a preferred embodiment, the molten mixture comprises a mixture of substantially crystalline drug particles suspended in a vehicle that is substantially fluid. In such cases, a portion of the drug can be dissolved in the fluid vehicle and a portion of the vehicle can remain solid. Although the term "fusion" refers specifically to the transition of a crystalline material from its crystalline state to its liquid state, what is known to occur at its melting point, and the term "molten" refers to such crystalline material in its liquid state, as used herein, the terms are used more widely. In the case of "fusion", the term refers to sufficient heating of any material! or mixture of materials so that it becomes fluid in the sense that it can be pumped or atomized in a similar manner to a crystalline material in a liquid state. Similarly, "molten" refers to any material or mixture of materials that is in such a fluid state. Practically any process can be used to form the molten mixture. One method involves melting the vehicle in a tank, adding the drug to the molten vehicle, and then mixing the mixture to ensure that the drug is evenly distributed therein. Alternatively, both the drug and the vehicle can be added to the tank and heated and mixed in the mixture to form the molten mixture. When the vehicle comprises more than one material, the molten mixture can be prepared using two tanks, melting a first vehicle in one tank and a second in another. The drug is added to one of these tanks and mixed as described above. In another method, a tank system in continuous agitation can be used, in which the drug and vehicle are added continuously to a heated tank provided with means for continuous mixing, while the molten mixture is continuously removed from the tank. An especially preferred process for forming the molten mixture is by means of an extruder. By "extruder" is meant a device or set of devices that creates a molten extrudate by heat and / or shearing forces and / or produces an extrudate mixed uniformly from a solid and / or liquid feed stream (per example, melted). Such devices include, but are not limited to, single screw extruders; double screw extruders, including extruders of joint rotation, counter rotating, intermeshing and non-intermeshing; multiple screw extruders; tamping extruders, consisting of a heated cylinder and a piston to extrude the molten feed stream; gear pump extruders, which consist of a heated gear pump, which generally rotates in the opposite direction, which simultaneously heats and pumps the molten feed stream; and conveyor extruders. The conveyor extruders comprise a transport means for transporting solid and / or powder feed streams, such as a screw conveyor or pneumatic conveyor, and a pump. At least a portion of the transport medium is heated to a temperature high enough to produce the molten mixture. The molten mixture can optionally be directed to an accumulation tank, before directing it to a pump that directs the molten mixture to an atomizer. Optionally, an in-line mixer can be used before or after the pump to ensure that the molten mixture is substantially homogeneous. In each of these extruders the molten mixture is mixed to form an extruded mixed uniformly. Said mixing can be achieved by various mechanical and processing means, which include mixing elements, kneading elements and countercurrent cutting mixing. Thus, in such devices, the composition is fed to the extruder, which produces a molten mixture that can be directed to the atomizer. When preparing the molten mixture in which the composition contains crystalline drug and the crystalline form of the drug comprises a volatile species having a vapor pressure of at least 0.01 atm (1.01 Kpa) at the maximum temperature of the mixture When melted, the drug can be maintained substantially in this way by ensuring that the activity of the volatile species in the molten mixture is high enough so that the volatile species is not substantially eliminated from the drug during the formation of the multiparticulates. Despite such precautions, a portion of such a crystalline drug can be dissolved in the molten vehicle and, upon dissolution, the volatile species will be partially removed from the drug. However, such precautions will increase the fraction of drug that remains in the crystalline state of drug with the volatile species. In order to keep the activity of the volatile species high in the molten mixture, it is desirable to maintain the gas phase atmosphere above the molten mixture at an elevated activity of the volatile species. This is more fully described in the commonly assigned U.S. patent application with the present serial number 60/527316 ("Method for Making Pharmaceutical Multiparticulates," No. of attorney's file PC25021), filed 4 December 2003. Once the molten mixture has been formed, it is administered to an atomizer that decomposes the molten feed stream into small droplets. Virtually any method can be used to administer the molten mixture to the atomizer, including the use of pumps and various types of pneumatic devices such as pressurized vessels or piston cups. When an extruder is used to form the molten mixture, the extruder itself can be used to deliver the molten mixture to the atomizer. Typically, the molten mixture is maintained at an elevated temperature while the mixture is delivered to the atomizer to prevent solidification of the mixture and to keep the molten mixture flowing. The feed stream is preferably melted before freezing for at least 5 seconds, more preferably at least 10 seconds, and most preferably at least 15 seconds so as to ensure adequate homogeneity of the drug / carrier melt. The molten mixture preferably also remains molten for no more than about 20 minutes to limit degradation of the drug. For some drug / vehicle combinations, it may be desirable to further reduce the time that the drug is in the melt mixture well below 20 minutes to further limit the degradation of the drug to an acceptable level. In such cases, such mixtures may be kept in the molten state for less than 15 minutes, and in some cases, even less than 10 minutes. When an extruder is used to produce the molten feed stream, the above times refer to the average time from when the material is introduced into the extruder until the molten mixture freezes. Such average times can be determined by methods known in the art. In an exemplary process, a small amount of dye or other marking substance is added to the feed stream while the extruder is operating under nominal conditions. The frozen multiparticulates are then collected over time and analyzed for the presence of dye or marking substance, from which the average time is determined. Generally, atomization occurs in one of several ways, including (1) by pressure or single fluid nozzles; (2) by two fluid nozzles; (3) by centrifugal or rotating disk atomizers; (4) by ultrasonic nozzles; and (5) by mechanical vibration nozzles. Detailed descriptions of atomization procedures can be found in Lefebvre, Atomization and Sprays (1989) or in Pen? 'S Chemical Engineers' Handbook, (7th Ed. 1997). Preferably, a centrifugal or rotary disk atomizer is used, such as the rotary atomizer FX1 of 100 mm manufactured by Niro A / S (Soeborg, Denmark). Once the molten mixture has been atomized, the droplets are frozen, typically by contact with a gas or liquid at a temperature below the solidification temperature of the droplets. Usually, it is desirable that the droplets freeze in less than about 60 seconds, preferably in less than about 10 seconds, and more preferably in less than about 1 second. Often, freezing at room temperature causes a sufficiently rapid solidification of the droplets forming suitable multiparticulates. However, the freezing step often occurs in a confined space to simplify the collection of multiparticulates. In such cases, the temperature of the freezing medium (either gas or liquid) will increase with time as the droplets are introduced into the closed space. Thus, a gas or coolant is often circulated through the enclosed space to maintain a constant freezing temperature. For some procedures, the gas or coolant can be cooled below room temperature to promote faster freezing. Suitable thermally based processes are more fully described in commonly assigned U.S. patent applications with the present serial number 60/527244 ("Improved Azithromycin Multiparticulate Dosage Forms by Melt-Congeal Processes," No. file PC25015), and 60/527315 ("Extrusion Processes for Forming Chemically Stable Drug Multiparticulates," file No. PC25122), filed on December 4, 2003. An agent that enhances mobility to multiparticulates may be incorporated during the procedure with thermal base. In a preferred process, the mobility enhancing agent can be mixed with a premix feed comprising the drug and one or more carriers; then the drug mixture, one or more vehicles and the mobility enhancing agent can be fed to an extruder which is used to form a molten mixture which is subsequently shaped into multiparticulates, as described above. The conditions for forming the multiparticulates are selected in such a way that a portion of the mobility promoting agent remains in the multiparticulates after formation. For example, if the mobility enhancing agent is water or ethanol, the temperature to form the multiparticulates is kept low enough so that a sufficient portion of the added water or ethanol remains in the multiparticulates. Alternatively, the method of formulating the multiparticulates is carried out in an atmosphere with a sufficient level of water vapor or ethanol vapor to prevent an unacceptably high loss of water or ethanol. Optionally, the multiparticulates can then be heated as described above to further stabilize their dissolution behavior.

In another preferred process, a mobility enhancing agent can be injected directly into an extruder which is used to form a molten feed stream comprising the drug and vehicle. As described above, the conditions for forming the multiparticulates are selected in such a way that a sufficient portion of the mobility enhancing agent is retained in the multiparticulates, which can then optionally be further treated by heating.

In another aspect, the multiparticulates are prepared by a liquid-based process comprising the steps of (a) forming a drug-comprising mixture, a pharmaceutically acceptable carrier, and a liquid; (b) forming particles from the mixture of step (a); and (c) removing a substantial portion of the liquid from the particles of step (b) forming multiparticulates. Preferably, step (b) is a process that is selected from (i) atomization of the mixture, (ii) coating of seed cores with the mixture, (iii) wet granulation of the mixture, and (iv) extrusion of mixing in a solid mass followed by spheronization or grinding of the dough. Preferably, the liquid has a boiling point of less than about 150 ° C. Examples of liquids suitable for the formation of multiparticulates using liquid-based processes include water; alcohols, such as methanol, ethanol, various isomers of propanol and various isomers of butanol; ketones, such as acetone, methyl ethyl ketone and methyl isobutyl ketone; hydrocarbons, such as pentane, hexane, heptane, cyclohexane, methylcyclohexane, octane and mineral oil; ethers, such as methyl tert-butyl ether, ethyl ether and ethylene glycol monoethyl ether; chlorocarbons, such as chloroform, methylene dichloride and ethylene dichloride; tetrahydrofuran; dimethylsulfoxide; N-methylpyrrolidinone; N, N-dimethylacetamide; acetonitrile; and its mixtures. In one embodiment, the particles are formed by atomizing the mixture using an appropriate nozzle to form small droplets of the mixture, which are sprayed in a drying chamber in which there is a large driving force to evaporate the liquid, producing solid particles generally spherical. The large driving force to evaporate the liquid is generally achieved by keeping the partial pressure of the liquid in the drying chamber well below the vapor pressure of the liquid at the temperature of the particles. This is achieved by (1) maintaining the pressure of the drying chamber at a partial vacuum (eg, from 0.01 (1.01 Kpa) to 0.5 atm (50.66 Kpa)); or (2) mixing the droplets with a tempered drying gas; or (3) both (1) and (2). Spray drying processes and spray drying apparatuses are described generally in Perry's Chemical Engineers' Handbook, pages 20-54 to 20-57 (6th Ed. 1984). In another embodiment, the particles are formed by coating seed cores with the liquid mixture. The seed cores may be formed of any suitable material such as starch, microcrystalline cellulose, sugar or wax, by any known method, such as melt freeze or spray freeze, extrusion / spheronization, granulation, spray drying and the like. The liquid mixture can be sprayed onto such seed cores using coating apparatus known in the pharmaceutical art, such as tray coaters (e.g., HiCoater available from Freund Corp. of Tokyo, Japan, Accela-Cota available from Manesty of Liverpool, UK. Kingdom), fluid bed coaters (e.g., Würster coaters or top spray coaters, available from Glatt Air Technologies, Inc. of Ramsey, New Jersey and Niro Pharma Systems of Bubendorf, Switzerland) and rotary granulators (e.g., CF -Granulator, available at Freund Corp). In another embodiment, the liquid mixture can be wet granulated to form the particles. Granulation is a process whereby relatively small particles are converted into larger granular particles, often with the help of a vehicle, also known as a binder in the pharmaceutical art. In wet granulation, a liquid is used to increase the intermolecular forces between the particles, which produces an enhancement of the granular integrity, which is termed the "strength" of the granule. Often, the strength of the granule is determined by the amount of liquid that is present in the interstitial spaces between the particles during the granulation process. When this is the case, it is important that the liquid moistens the particles, ideally with a zero contact angle. Examples of liquids that have been found to be effective liquids for wet granulation include water, ethanol, isopropyl alcohol and acetone. Various types of wet granulation processes can be used to form multiparticulates containing drugs. Examples include fluid bed granulation, rotary granulation and high cut rate mixers. In fluid bed granulation, air is used to agitate or "fluidize" the drug and / or vehicle particles in a fluidization chamber. The liquid is then sprayed into this fluid bed, forming the granules. In the rotary granulation, horizontal discs rotate at high speed, forming a rotating "rope" of drug particles and / or vehicle in the walls of the granulation container. The liquid is pulverized to this rope, forming the granules. High shear rate mixers contain an agitator or impeller to mix the drug and / or vehicle particles. The liquid is sprayed into the bed of moving particles, forming granules. In these procedures, all or a portion of the vehicle can be dissolved in the liquid before spraying the liquid onto the particles. Thus, in these processes, the steps of forming the liquid mixture and the formation of particles from the liquid mixture are produced simultaneously. In another embodiment, the particles are formed by extruding the liquid mixture into a solid mass followed by spheronization or grinding of the dough. In this process, the liquid mixture, which is in the form of a paste-like plastic suspension, is extruded through a perforated plate or nozzle forming a solid mass, often in the form of elongated solid rods. This solid mass is then ground to form the multiparticulates. In one embodiment, the solid mass is placed, with or without an intermediate drying step, on a rotating disk having protrusions that disintegrate into material by forming spheres, spheroids or rounded multiparticulate rods. The multiparticulates thus formed are then dried by removing any remaining liquid. This process is sometimes referred to in the extrusion / spheronization process as the pharmaceutical technique. Once the particles are formed, a portion of the liquid is removed, typically in a drying step, thus forming the multiparticulate. Preferably, at least 80% of the liquid in the particles is removed, more preferably at least 90%, and most preferably at least 95% of the liquid is removed from the particles during the drying step. Suitable liquid-based processes are described in more detail in the commonly assigned U.S. patent application Serial No. 60/527405 ("Improved Azithromycin Multiparticulate Dosage Forms by Liquid-Based Processes," No. attorney's file PC25018) filed on December 4, 2003. A mobility-enhancing agent prepared by a liquid-based process can be incorporated into the multiparticulates. In such exemplary procedure, the mobility promoting agent can be mixed with a drug, one or more vehicles, and a liquid forming a mixture. Then particles are formed from the mixture, and the liquid is subsequently removed by forming the multiparticulates, as described above. The processing conditions are chosen in a way that ensures that a portion of the agent that enhances mobility is retained in the multiparticulates after training.; optionally the multiparticulates can be heated afterwards to further improve the stability. Multiparticulates can also be prepared by a granulation process comprising the steps of (a) forming a solid mixture comprising a drug and a pharmaceutically acceptable carrier; and (b) granulating the solid mixture into multiparticulates. Examples of such granulation processes include dry granulation and melt granulation, well known in the art. See, for example, Remington's Pharmaceutical Sciences (18th Ed. 1990). An example of a dry granulation process is roller compaction, in which the solid mixture is compressed between rollers. The rollers may be designed so that the resulting compressed material is in the form of beads or small granules of the desired diameter. Alternatively, the compressed material is in the form of a tape that can be milled to form multiparticulates using procedures well known in the art. See Remington's Pharmaceutical Sciences (16th Ed. 1980). In the processes of granulation in the molten state, the solid mixture is fed to a granulator which has the ability to heat or melt the vehicle. Apparatus suitable for use in this process include high-cut-rate pelletizers or single-screw or multi-screw extruders such as those described above for melt-freezing processes. In the melt granulation processes, the solid mixture is introduced into the granulator and heated until the solid mixture forms an agglomerate. The solid mixture is then kneaded or mixed until the desired particle size is obtained. The granules thus formed are then cooled, removed from the granulator and sieved to the fraction of desired size, thus forming the multiparticulates. Improved Stability In addition to increasing the crystallinity of the drug in the multiparticulate, in one embodiment, the post-treatment process is carried out for a sufficiently long time to allow the multiparticulates to reach a sufficiently stable low energy state. Thus, the multiparticulates subjected to further processing by the process of the present invention have improved stability compared to that of the multiparticulates of control which have essentially the same composition but not subjected to further treatment by the process of the present invention. Multiparticulates can show any or all of the following improvements in stability: (1) physical, which means either (a) the fraction of drug in its crystalline state of lower energy or the fraction of drug in the crystalline state in which was the drug before the formation of the multiparticulates in the multiparticulate subject to further treatment is greater than that of the control, (b) the rate of change in the crystalline state of the drug and / or vehicle in the multiparticulate subject to further treatment is lower that the rate of change in the multiparticulate control, or (c) both (a) and (b); or (2) chemistry, which means a reduction in the rate of degradation or reaction of the drug; or (3) related to the dissolution behavior, which means a reduction in the rate of change of the dissolution behavior of the drug. The improvement of physical stability can be determined by comparing the crystallinity of the drug in a multiparticulate subjected to further treatment, with the crystallinity of the drug in the multiparticulate control. Often, the drug can exist in more than one crystalline form. In such cases, one form, or polymorph, is usually preferred to the other forms. Often, the form with the lowest energy is desired because it is the most physically and chemically stable. In some cases, the initial form of the drug before forming the multiparticulates is the desired form. For example, normally, for azithromycin, the crystalline dihydrate form is preferred. In such cases, the post-treatment procedure may provide an increase in the fraction of drug present in the multiparticulates in the lower energy crystalline form or an increase in the fraction of drug present in the initial crystalline form. A relative degree of improvement of the crystalline form of the drug can be used to measure improvements in this aspect of the invention. By "relative degree of improvement of the crystalline form of the drug" is meant the ratio between (1) the amount of drug that is not in the desired crystalline form in the multiparticulate control and (2) the amount of drug that is not in the desired crystalline form in a multiparticulate subjected to further treatment. For example, if the amount of the crystalline drug form with the lowest energy in the multiparticulate control is 80% by weight and the amount of the crystalline drug form with the lowest energy in the multiparticulate subjected to further treatment is 90% by weight, the relative degree of improvement of the crystallinity is (100% by weight - 80% by weight) / (100% by weight - 90% by weight) = 20% by weight / 10% by weight = 2 , 0. Similarly, if the amount of drug present as the initial crystalline form of the drug in the multiparticulate control is 80% by weight and the amount of the initial crystalline form of the drug in the multiparticulate subjected to further treatment is 90% by weight. weight, the relative degree of improvement of the crystalline form of the drug is (100% by weight - 80% by weight) / (100% by weight -90% by weight) = 20% by weight / 10% by weight = 2, 0 A composition is inside! scope of this ct of the invention if the post-treatment process produces a relative degree of improvement of the crystalline form of the drug, determined by one or more of the above processes, of at least 1.25, preferably at least 1.5; and more preferably at least 2.0. Alternatively, an improvement in physical stability can be determined by comparing the rate of change of the crystalline state of the drug or vehicle in a multiparticulate subjected to further treatment, with the rate of change of the crystalline state of the drug or vehicle in a multiparticulate control. The inventors have found that during the subsequent treatment process, the crystalline state of the drug or vehicle will change to a lower energy state. After reaching the lowest energy state, changes in the form of the drug or vehicle occur much more slowly. For multiparticulates not subjected to further treatment, the transition to a lower energy state occurs during the storage interval. As a result, the rate of change in the crystalline state of the drug or vehicle will be slower for a multiparticulate subject to further treatment than for a multiparticulate control. Such changes in the crystalline state of the drug or vehicle can be measured by any standard physical measurement, such as PXRD, DSC (differential scanning calorimetry), solid state NMR or scanning electron microscopy ("SEM"), preferably by the PXRD procedure described above. Preferably, the rate of change of the crystalline state of the drug or vehicle of the multiparticulate subject to further treatment is less than 80%, and more preferably less than 67%, of the rate of change of the multiparticulate control. Thus, for example, if the vehicle of the control multiparticulate changes from a polymorph of high energy to a polymorph of low energy at a speed of 30% per year, the vehicle of the multiparticulate subject to further processing will change at a rate of less than 24. % per year, preferably less than 20% per year. Often, much more dramatic improvements are observed, such as less than about 10% of the rate of change of the control multiparticulate, or less than about 3% per year for the example that is provided. Thus, another method to determine the improvement of the physical stability of a multiparticulate is to determine the relative degree of improvement in the change of the crystalline state to the multiparticulate, which means the relation between (1) the rate of change of the crystalline state of the drug. or vehicle in a multiparticulate control and (2) the rate of change of the crystalline state of the drug or vehicle in a multiparticulate subjected to further treatment. For example, when the speed of change in the crystalline state of a vehicle in the multiparticulate subject to further treatment is 4% by weight per year, and the rate of change in the crystalline state of a vehicle of the multiparticulate control is 5%. % in weight per year, the relative degree of improvement is 5/4, or 1.25. Preferably, the relative degree of improvement in the crystalline state change is at least 1.25, preferably at least 1.5, and more preferably 2. In another ct of the invention, the drug in the multiparticulate subjected to further treatment has stability improved chemistry compared to the drug in the multiparticulate control. The multiparticulates subjected to further treatment and control are the same as those indicated above for physical stability. As used in the present document; "Chemical stability" refers to the rate of chemical degradation of the drug in a typical storage environment. Types of chemical degradation reactions that may occur include, but are not limited to, hydrolysis, lactonization, esterification, oxidation, reduction, ring delation and transesterification. The drug in a chemically stable multiparticulate subjected to further treatment has a reduced degradation rate compared to a drug in the multiparticulate control. In general, drug degradation can be measured using any conventional method for measuring the purity or potency of a drug in a pharmaceutical composition. For example, the amount of active drug present in a multiparticulate can be measured initially using high performance liquid chromatography (HPLC) or other analytical techniques known in the art. Alternatively, the amount of drug present initially can be calculated from the amount of drug present in the multiparticulate formulation. The power of the multiparticulate is then measured after storage under controlled temperature and humidity conditions for an appropriate period of time. A decrease in potency indicates that a chemical reaction has occurred, which produces a decrease in the amount of active drug present in the multiparticulate and is an indicator of poor chemical stability. An alternative procedure that is used to assess chemical stability is to analyze the rate of increase of the amount of product (s) of drug degradation in the multiparticulate, which would indicate drug reaction. HPLC or other analytical techniques can be used to determine the concentration of drug degradation product (s) of a multiparticulate. The amount of the degradation product (s) is measured before and after storage under controlled storage conditions. The amount of increase of the drug degradation product (s) can be used to determine the amount of decrease in the "percentage purity of the drug", which is defined as 100 times the total amount of drug present divided by the amount of drug. drug present initially. Thus, the percentage purity of the drug can be calculated as follows: percentage purity of the drug = 100 x (total drug present / drug initially present) When the purity of the drug is calculated from the total amount of impurities, the percentage purity of the The drug can be calculated assuming that the drug present initially, expressed in% by weight, is equal to 100% by weight minus% by weight of the total initial impurities, and that the total present drug is equal to 100% by weight less % by weight of total impurities after storage, that is, at a later time. This procedure for calculating the percentage purity of the drug is by the formula: percentage purity of the drug = 100 x [1- [total impurities / drug present initially]] The rate at which drug degradation occurs is generally dependent on the storage conditions. The drug, when formulated in a multiparticulate of the present invention, should be stable under ambient temperature and humidity conditions (eg, 20% to 60% RH) for extended periods of time, such as months or years. However, to accelerate the tests, storage conditions can employ high temperature and / or humidity to simulate longer storage times under environmental conditions. The storage time can vary from a few days to weeks or months, depending on the reactivity of the drug and the storage conditions. A "degree of degradation" of the drug after storage can be determined by subtracting the final percentage purity of the drug (which is determined either by measuring the decrease in the drug present or the increase in drug impurities present) of the initial percentage purity of the drug. For example, a sample of multiparticulates that initially contains 100 mg of drug and that has no quantifiable impurities would have an initial percentage purity of the drug of 100% by weight. Yes, after storage, the amount of drug in the sample drops to 95 mg, the final percentage purity of the drug would be 95% by weight and the degree of degradation would be 100% by weight minus 95% by weight, or 5% by weight. weight. Alternatively, if it were found that 100 mg of drug substance initially had 1 mg of impurities present, it would have an initial percentage purity of the drug of 99% by weight. If, after storage, the total impurities present had increased to 6% by weight, the final percentage purity of the drug would be 94% by weight and the degree of degradation would be 99% by weight minus 94% by weight, or 5% in weigh. Alternatively, the degree of degradation can be determined by subtracting the amount of one or more specific degradation products of the drug initially present from the amount of that specific degradation product present after storage. Such a measurement is useful when there are several drug degradation products, of which only one or a few are interesting. For example, if a drug initially contained a specific degradation product at a concentration of 1% by weight and after storage the concentration of that degradation product was 6% by weight, the degree of degradation would be 6% by weight minus 1 % by weight, or 5% by weight. A relative degree of improvement of chemical stability can be determined by taking the ratio between the degree of degradation of the drug in a multiparticulate control and the degree of degradation of the drug in a multiparticulate subjected to further treatment under the same storage conditions during the same period of storage time. For example, when the degree of degradation of a drug in the multiparticulate subjected to further treatment is 1% by weight, and the degree of degradation of the multiparticulate control is 50% by weight, the relative degree of improvement is 50% by weight / 1% by weight, or 50. For multiparticulates of this aspect of the invention, the relative degree of improvement is at least 1.25. When the drug is particularly unstable, higher relative degrees of improvement may be necessary, so that the chemical stability of the multiparticulate is pharmaceutically acceptable. In such cases, the invention provides greater chemical stability when the relative degree of improvement is at least about 2, preferably at least about 5, and most preferably at least 10. In fact, some multiparticulates can achieve a relative degree of improvement of chemical stability greater than 100. Particular storage conditions and storage time for testing can be chosen as appropriate depending on the stability of the drug, the particular vehicle being used, and the relationship between the drug and the vehicle in the multiparticulate When the drug is particularly unstable, or when the multiparticulate has a low drug to carrier ratio, then shorter storage times may be used. When the rate of degradation of the drug is linear, the degree of relative improvement will be independent of the storage time. However, when the rate of degradation of the drug is not linear under controlled storage conditions, the stability test that is used to compare the multiparicle undergoing further treatment with the control multiparticulate is preferably chosen in such a way that the degree of degradation is large enough so that it can be measured accurately. Typically, the period of time is chosen such that a degree of degradation of at least 0.1 to 0.2% by weight is observed. Nevertheless; The period of time should not be so long that the relationship between drug and vehicle changes substantially. Typically, the period of time is such that the degree of degradation observed for the multiparticulate subjected to further treatment is less than 50% by weight and preferably less than 20% by weight. When the rate of degradation of the drug in the control multiparticulate is relatively slow, the test preferably is performed for a sufficiently long period of time under controlled storage conditions to allow a meaningful comparison between the stability of the multiparticulate subjected to further treatment and the multiparticulate control. The multiparticulate drug subjected to further treatment may have a degree of degradation of less than about 5% by weight preferably less than about 1% by weight, more preferably less than about 0.5% by weight, and most preferably less than about 0.1% by weight when stored at 40 ° C and 75% RH for six months; or less than about 5% by weight, preferably less than about 1% by weight, more preferably less than about 0.5% by weight, and most preferably less than about 0.1% by weight, when stored at 30 °. C and 60% RH during one year; or less than about 5% by weight, preferably less than about 1% by weight, more preferably less than about 0.5% by weight, and most preferably less than about 0.1% by weight when stored under ambient conditions during two years or at 25 ° C and 60% RH for 2 years. Despite these preferred degrees of degradation, the multiparticulates of the invention can have a degree of degradation that is much greater than the preferred values, insofar as the multiparticulates subjected to further treatment achieve the degree of improvement compared with the multiparticulates of control as described above. In another aspect of the invention, the compositions of the invention have improved stability in dissolution performance. This can be determined by comparing the rate of change of the dissolution behavior of the drug in a multiparticulate subjected to further treatment with the rate of change of the dissolution behavior of the drug in the multiparticulate control. First, after the formation of the multiparticulates, the dissolving behavior of multiparticulates subjected to further treatment and of the multiparticulates of control is determined at least for two time points that are sufficiently distant to observe a change in the behavior in the multiparticulate of control and to define a period of time. Such period of time is typically at least one day and more typically 1-12 weeks. Storage periods can be up to 2 years. The dissolution behavior can be compared either with the dissolution rate constant (as defined below), or with the amount of drug released after a period of time. A percentage change in dissolution behavior is calculated based on the dissolution behavior in both times. For example, if a mulíiparticulado subjected to subsequent treatment initially provides a first order dissolution speed constant at time 0 of 0.010 minutes "1 and a year later provides a dissolution rate constant of 0.008 minutes" 1, the percentage change of the dissolution behavior would be [(0.010 min "1 -0.008 min" 1) / 0.01 min'1)] x 100, or 20%. Similarly, if the multiparticulate undergoing subsequent treatment initially released 50% of the drug at 30 minutes and, a year later, released 40% of the drug at 30 minutes, the percentage change in dissolution behavior would be [(50% - 40%) / 50%] x 100, or 20%. A relative degree of improvement of the stability of the dissolution behavior can be determined by taking the ratio between the percentage change in the dissolution behavior of the control multiparticulate and the percentage change in the dissolution behavior of the multiparticulate subjected to further treatment in the same storage conditions during The same period of storage time. For example, when the percentage change in the dissolution behavior of the control multiparticulate is 20%, and the percentage change in the dissolution behavior of the multiparticulate subjected to subsequent treatment is 10%, the relative degree of improvement of the dissolution behavior is 20% / 10% , or 2. For a multiparticulate of this aspect of the present invention, the relative degree of improvement of the stability of the dissolution behavior is at least 1.25. The relative degree of improvement of the dissolution behavior may be greater than 2, or may be even greater than 4. The particular storage conditions and storage time for evaluating the physical, chemical, or dissolving behavior may be chosen as appropriate. convenient. A stability test that can be used to analyze whether a composition meets the stability criteria described is to store the multiparticulate subjected to further treatment and the multiparticulate control for three weeks at 40 ° C and 75% RH. A relative degree of improvement can be made clear in a shorter time, such as three to five days, and shorter storage times can be used for some drugs. When comparing compositions under storage conditions that approximate environmental conditions, eg, 25 ° C and 60% RH, it may be necessary for the storage period to be several months up to two years. Drugs The multiparticulates of the present invention include a drug. Preferably, the drug accounts for at least 10% by weight of the total weight of the multiparticulate, more preferably at least 20% by weight, and most preferably at least 40% by weight. The term "drug" as used herein includes, by way of example and not limitation, any physiologically or pharmacologically active substance that produces a localized or systemic effect in animals. The term "animals" is intended to include mammals, including humans as well as other animals. Examples of drugs that are employed in the devices of this invention include, without limitation, inorganic and organic compounds that act on the peripheral nerves, adrenergic receptors, cholinergic receptors, nervous system, skeletal muscles, cardiovascular smooth muscles, blood circulatory system, synaptic zones , neuroeffector binding sites, endocrine and hormonal systems, immunogenic system, reproductive system, auiocoid systems, food and excretory systems, inhibitors of autocoid systems and histamine systems. Preferred drug classes include, but are not limited to, antihypertensive agents, anxiolytic agents, anticoagulant agents, anticonvulsants, blood glucose lowering agents, decongestants, antihistamines, antitussives, antineoplastics, beta-blockers, anti-inflammatories, antipsychotic agents, cognitive enhancers, anti-inflammatory agents, atherosclerosis, cholesterol lowering agents, anti-obesity agents, agents., against autoimmune disorders, anti-impotence agents, anti-incontinence agents, antibacterial and antifungal agents, hypnotic agents, anti-Parkinson's agents, agents against Alzheimer's disease, antibiotics, antidepressants, antiviral agents, inhibitors of glycogen phosphorylase and inhibitors of the transfer proteins of cholesterol esters. Each named drug should be understood to include the neutral form of the drug and its pharmaceutically acceptable forms. By their "pharmaceutically acceptable forms" is meant any pharmaceutically acceptable derivative or variation, which includes stereoisomers, mixtures of stereoisomers, enantiomers, solvates, hydrates, isomorphs, polymorphs, salt forms and prodrugs. Specific examples of antihypertensives include prazosin, nifedipine, amlodipine besylate, trimazosin and doxazosin; Specific examples of a blood glucose lowering agent are glipizide and chloropropamide; a specific example of an agent against impotence is sildenafil and sildenafil citrate; specific examples of antineoplastics include chlorambucil, lomustine and equinomycin; a specific example of an imidazole type antineoplastic is tubulazole; a specific example of an antihypercholesterolemic is atorvastatin and atorvastatin calcium; specific examples of anxiolytics include hydroxyzine hydrochloride and doxepin hydrochloride; Specific examples of anti-inflammatory agents include betamethasone, prednisolone, aspirin, piroxicam, valdecoxib, carprofen, celecoxib, flurbiprofen and (+) - N-. { 4- [3- (4-fluorophenoxy) phenoxy] -2-cyclopenten-1-yl} -N-hydroxyurea; a specific example of a barbiturate is phenobarbital; specific examples of antivirals include acyclovir, nelfinavir and virazole; specific examples of vitamins / nutritional agents include retinol and vitamin E; specific examples of beta-blockers include timolol and nadolol; A specific example of an emetic is apomorphine; Specific examples of a diuretic include chlorthalidone and spironolactone; a specific example of an anticoagulant is dicumarol; specific examples of cardiotonics include digoxin and digitoxin; Specific examples of androgens include 17-methyltestosterone and testosterone; a specific example of a mineral corticoid is deoxycorticosterone; A specific example of a hypnotic / anesthetic steroid is alphaxalone; Specific examples of anabolic agents include fluoxymesterone and methanestenolone, specific examples of antidepressant agents include sulpiride, [3,6-dimethyl-2- (2,4,6-trimethylphenoxy) pyridin-4-yl] - (1-ethylpropyl) amine, 3,5-dimethyl-4- (3, -pentoxy) -2- (2,, 4,, 6, -trimethylphenoxy) pyridine, piroxidine, fluoxetine, paroxetine, venlafaxine and sertraline; Specific examples of antibiotics include carbenicillin, indanyl sodium, bacampicillin hydrochloride, troleandomycin, doxycycline hyclate, ampicillin, amoxicillin, and penicillin G; specific examples of anti-infectives include benzalkonium chloride and chlorhexidine; Specific examples of coronary vasodilators include nitroglycerin and myoflazine; a specific example of a hypnotic is etomidate; Specific examples of carbonic anhydrase inhibitors include acetazolamide and chlorzolamide; Specific examples of antifungals include econazole, terconazole, fluconazole, voriconazo !, and griseofulvin; a specific example of an antiprotozoal agent is metronidazole; specific examples of anthelminthic agents include thiabendazole and oxfendazole and morantel; specific examples of antihistamines include astemizole, levocabastine, cetirizine, descarboethoxyloratadine and cinnarizine; Specific examples of antipsychotics include ziprasidone, olanzepine, thiothixene hydrochloride, fluspirilene, risperidone and penfluridol; specific examples of gastrointestinal agents include loperamide and cisapride; specific examples of serotonin antagonists include ketanserin and mianserin; A specific example of an anesthetic is lidocaine; a specific example of a hypoglycemic agent is acetohexamide; a specific example of an antiemetic is dimenhydrinate; a specific example of an antibacterial is cotrimoxazole; a specific example of a dopaminergic agent is L-DOPA; Specific examples of agents against Alzheimer's disease are THA and donepezil; a specific example of an antiulcer agent / H2 antagonist is famotidine; specific examples of sedative / hypnotic agents include chlordiazepoxide and triazolam; a specific example of a vasodilator is alprostadil; a specific example of a platelet inhibitor is prostacyclin; specific examples of ACE inhibitors / antihypertensive agents include enalaprilic acid, quinapril, and lisinopril; Specific examples of tetracycline antibiotics include oxytetracycline and minocycline; Specific examples of macrolide antibiotics include erythromycin, clarithromycin and spiramycin; A specific example of an azalide antibiotic is azithromycin; Specific examples of glycogen phosphorylase inhibitors include [R- (R * S *)] - 5-chloro-N- [2-hydroxy-3 (methoxymethylamino) -3-oxo-1- (phenylmethyl) -protyl-1H- indole-2-carboxamide and [(1S) -benzyl- (2R) -hydroxy-3- ((3R, 4S) -dihydroxy-pyrro! idin-1-yl) -3-oxypropyl] -amide of the acid -chloro-1 H-indole-2-carbolic acid; and specific examples of inhibitors of cholesterol ester transfer proteins include [2R, 4S] -4- [acetyl- (3,5-bis-trifluoromethylbenzyl) amino] -2-ethyl isopropyl ester. -6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester [2R, 4S] -4- [3,5-bis-trifluoromethylbenzyl] methoxycarbonylamino] -2-ethyl -6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid and [2R, 4S] -4 - [(3,5-bis-trifluoromethylbenzyl) methoxycarbonyl-amino acid] -2- isopropyl ester -ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinolin-1-carboxylic acid. A preferred drug for use with the present invention is azithromycin. Azithromycin is the generic name for the drug 9a-aza-9a-methyl-9-deoxo-9a-homoerythromycin A, a broad-spectrum antimicrobial compound derived from erythromycin A. Accordingly, azithromycin and certain derivatives thereof are useful as antibiotics The drug may be in the form of the free base, a pharmaceutically acceptable salt or a prodrug. The drug can also be in its anhydrous, hydrated or solvated forms. The invention is intended to encompass all these forms. The azithromycin present in the multiparticulates of the present invention is preferably crystalline, including any crystalline polymorph. The various polymorphs of crystalline azithromycin are described in the publication of patent application for transfer and common processing with the present n ° 20030162730, published on August 28, 2003; U.S. Patent Nos. 6,365,574 and 6,245,903; U.S. Patent Application Publication Nos. 20010047089, published November 29, 2001, and 20020111318, published August 15, 2002; and International Patent Application Publication Nos. WO 01/00640; WO 01/49697, WO 02/10181 and WO 02/42315. In a preferred embodiment, azithromycin is in the form of the crystalline dihydrate, which is described in U.S. Patent No. 6,268,489. Vehicles Multiparticulates prepared by the process of the present invention include a pharmaceutically acceptable carrier. By "pharmaceutically acceptable" it is meant that the vehicle must be compatible with the other ingredients of the composition, and not deleterious to the recipient thereof. Generally, the vehicle is selected to keep the degradation products at acceptable levels. The vehicle functions as a matrix for the multiparticulate or affecting the rate of release of the drug from the multiparticulates, or both. The vehicle may consist of a single material, or may be a mixture or combination of materials. Examples of suitable vehicles for use in the multiparticulates of the present invention include long chain alcohols, such as stearyl alcohol, cetyl alcohol and polyethylene glycol; esters of long chain fatty acids, such as glyceryl monooleate, glyceryl monostearate, glyceryl palmito stearate, polyethoxylated castor oil derivatives, hydrogenated vegetable oils, monoalkyl glycerides, dialkyl glycerides, and trialkyl glycerides, and monobenenates, dibenates, and tribenates of glyceryl; waxes, such as synthetic wax, microcrystalline wax, paraffin wax, carnauba wax, and white and yellow beeswax; cellulosics substituted with ethers, such as microcrystalline cellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and ethylcellulose; cellulosics substituted with esters, such as cellulose acetate, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, cellulose acetate trimellitate, and hydroxypropylmethylcellulose acetate succinate; and polymethacrylates and polyacrylates functionalized with acids or esters. Mixtures and combinations of such materials can also be used. Vehicles that are used in the multiparticulates prepared by the present invention will generally be from about 10% by weight to about 95% by weight of the multiparticulate, preferably from about 20% by weight to about 90% by weight of the multiparticulate, and most preferably from about 40% by weight to about 70% by weight of the multiparticulates, based on the total mass of the multiparticulate. The vehicles are preferably solid at temperatures of about 40 ° C. The inventors have found that if the vehicle is not solid at 40 ° C, changes in the physical characteristics of the composition can occur over time, especially when stored at elevated temperatures, such as at 40 ° C. Thus, it is preferred that the vehicle be solid at a temperature of about 50 ° C, more preferably about 60 ° C. Optional Excipients Multiparticulates may optionally include excipients to aid in the formation of the multiparticulates, to affect the rate of release of azithromycin from the multiparticulates, or for other purposes known in the art. Multiparticulates may optionally include a dissolution enhancer. The dissolution enhancers increase the rate of dissolution of the drug from the vehicle. In general, the solubilizers of the solution are amphiphilic compounds and are generally more hydrophilic than the vehicle. The enhancers of the solution will generally assume from about 0.1 to about 30% by weight of the total mass of the multiparticulate. Exemplary dissolving enhancers include alcohols such as stearyl alcohol, cetyl alcohol, and polyethylene glycol; surfactants such as poloxamers (such as poloxamer 188, poloxamer 237, poloxamer 338, and poloxamer 407), docusate salts, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polysorbabies, polyoxyethylene alkyl esters, sodium lauryl sulfate, and sorbitan monoesters; sugars such as glucose, sucrose, xylitol, sorbitol, and maltitol; salts such as sodium chloride, potassium chloride, lithium chloride, calcium chloride, magnesium chloride, sodium sulfate, potassium sulfate, sodium carbonate, magnesium sulfate, and potassium phosphate; amino acids such as alanine and glycine; and its mixtures. Although not wishing to be bound by any particular theory or mechanism, it is believed that the dissolution enhancers present in the multiparticulates affect the rate at which the aqueous environment of use penetrates the multiparticulate, thus affecting the rate at which the drug is released. In addition, such agents can improve the rate of drug release by aiding in the dissolution in water of the vehicle itself, often solubilizing the vehicle in micelles. Preferably, the dissolution enhancer is a surfactant, and most preferably, the dissolution enhancer is a poloxamer. Agents that inhibit or retard the release of the drug from the multiparticulates can also be included in the vehicle. Such agents that inhibit dissolution are generally hydrophobic. Examples of agents that inhibit dissolution include: dialkyl phthalates such as dibutyl phthalate, hydrocarbon waxes such as microcrystalline wax and paraffin wax; and polyethylene glycols having molecular weights greater than about 20,000 daltons. Another useful class of excipients, especially when the multiparticulates are prepared by thermally based processes, are the materials that are used to adjust the viscosity of the molten mixture that is used to form the multiparticulates. Such viscosity adjusting excipients will generally assume from 0 to 25% by weight of the multiparticulate, based on the total mass of the multiparticulate. The viscosity of the molten mixture is a key variable in obtaining multiparticulates with a narrow particle size distribution. For example, when a rotary disk atomizer is employed, it is preferred that the viscosity of the molten mixture be at least about 1 cp (1 mPa-s) and less than about 10,000 cp (10,000 mPa-s), more preferably at least 50 cp (50 mPa-s) and less than approximately 1000 cp (1000 mPa-s). If the molten mixture has a viscosity outside these preferred ranges, a viscosity adjusting vehicle may be added to obtain a molten mixture in the preferred viscosity range. Examples of excipients that reduce viscosity include stearyl alcohol, cetyl alcohol, low molecular weight polyethylene glycol (e.g., less than about 1000 daltons), isopropyl alcohol, and water. Examples of excipients that increase viscosity include microcrystalline wax, paraffin wax, synthetic wax, high molecular weight polyethylene glycols (eg, greater than about 5000 daltons), ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, silicon dioxide, microcrystalline cellulose, silicate magnesium, sugars, and salts. Other excipients may be added to adjust the release characteristics from the multiparticulates or to improve the processing and typically will assume from 0 to 50% by weight of the multiparticulate, based on the total mass of the multiparticulate. For example, for basic drugs, such as azithromycin, the solubility in an aqueous solution decreases with increasing pH; therefore, a base in the composition can be included to decrease the rate at which the drug is released in an aqueous use environment. Examples of bases that may be included in the composition include dibasic and tribasic sodium phosphate, dibasic and tribasic calcium phosphate, monoethanolamine, dietanofamine, and trietapolamine, sodium bicarbonate, sodium citrate dihydrate, and methacrylate polymers and copolymers with amine functions, such as EUDRAGIT E100 ® from Rohm GmbH as well as other salts of oxides, hydroxides, phosphates, carbonates, bicarbonates and citrates, including hydrated and anhydrous forms known in the art. Still other excipients can be added to reduce the static charge of the multiparticulates; examples of such antistatic agents include talc and silicon dioxide. Aromas, colorants and other excipients may also be added in their usual amounts for the usual purposes. In one embodiment, the vehicle and one or more optional excipients form a solid solution, which means that the vehicle and one or more optional excipients form a single thermodynamically stable phase. When a thermally based process, such as melt freezing, is used to form the multiparticulates, the vehicle / carrier mixture can be completely melted at the processing temperatures that are used to form multiparticulates or a material can be solid while that the other (s) are melted, producing a suspension of a material in the molten mixture. When the vehicle and one or more optional excipients do not form a solid solution but are desired to be so, for example, to obtain a specific controlled release profile, a third excipient may be included in the composition producing a solid solution comprising the vehicle, the one or more optional excipients, and the third excipient. For example, it may be desirable to use microcrystalline wax and a surfactant, such as poloxamer, to obtain a multiparticulate with the desired release profile. In such cases no solid solution is formed, in part due to the hydrophobic nature of the microcrystalline wax and the hydrophilic nature of the poloxamer. By including a small amount of a third component, such as stearyl alcohol, in the formulation, a solid solution can be obtained by producing a multiparticulate with the desired release profile. In one aspect, the multiparticulates are in the form of a matrix that does not disintegrate. By "non-disintegrating matrix" it is meant that at least a portion of the vehicle does not dissolve or disintegrate after introducing the multiparticulates in an aqueous use environment. In such cases, the drug and optionally a portion of one or more optional excipients, for example, a dissolution enhancer, are removed from the multiparticulate by dissolution. At least a portion of the vehicle does not dissolve or disintegrate and is excreted when the environment of use is in vivo, or remains suspended in an experimental solution when the environment of use is in vitro. In this aspect, it is preferred that at least a portion of the vehicle have a low solubility in the aqueous use environment. Preferably, the solubility of the vehicle in the aqueous use environment is less than about 1 mg / ml, more preferably less than about 0.1 mg / ml, and most preferably less than about 0.01 mg / ml. Examples of suitable low solubility vehicles include waxes, such as synthetic wax, microcrystalline wax, paraffin wax, carnauba wax, and beeswax; glycerides, such as glyceryl monooleate, glyceryl monostearate, glyceryl palmito stearate, monobehenates, dibenates, and glyceryl tribenates, glyceryl tristearate, glyceryl tripalmitate; and its mixtures. In one embodiment, the multiparticulate comprises from about 20 to about 75% by weight of drug, from about 25 to about 80% by weight of a carrier, and from about 0.1 to about 30% by weight of a dissolution enhancer. based on the total mass of the multiparticulate. In a preferred embodiment, the multiparticulate comprises from about 35% by weight to about 55% by weight of drug; from about 40% by weight to about 65% by weight of an excipient that is selected from waxes, such as synthetic wax, microcrystalline wax, paraffin wax, carnauba wax, and beeswax; glycerides, such as glyceryl monooleate, glyceryl monostearate, glyceryl palmito stearate, polyethoxylated castor oil derivatives, hydrogenated vegetable oils; glyceryl monobehenates, dibenates, and tribenates, glyceryl tristearate, glyceryl tripalmitate; and its mixtures; and from about 0.1 to about 15% by weight of a solution enhancer that is selected from surfactants, such as poloxamers, polyoxyethylene alkyl ethers, polysorbates, polyoxyethylene alkyl esters, sodium lauryl sulfate, and sorbitan monoesters; alcohols, such as stearyl alcohol, cetyl alcohol, and polyethylene glycol; sugars such as glucose, sucrose, xylitol, sorbitol, and maltitol; salts such as sodium chloride, potassium chloride, lithium chloride, calcium chloride, magnesium chloride, sodium sulfate, potassium sulfate, sodium carbonate, magnesium sulfate, and potassium phosphate; amino acids such as alanine and glycine; and its mixtures. In another embodiment, the multiparticulates of the present invention comprise (a) a drug; (b) a glyceride carrier having at least one 16 p alkylate substituent plus carbon atoms; and (c) a polyoxyethylene and polyoxypropylene block copolymer (poloxamer). At least 70% by weight of the multiparticulate drug is crystalline. Small changes in the relative amounts of the glyceride vehicle and the poloxamer produce large changes in the rate of drug release. This allows to precisely control the rate of drug release from the multiparticulate, selecting the appropriate ratio between drug, glyceride vehicle and poloxamer. These vehicles have the additional advantage of releasing almost all the drug from the multiparticulate. Such multiparticulates are more fully described in the commonly assigned U.S. patent application herein under serial no. 60/527329 ("Multiparticulate Crystalline Drug Compositions Having Controlled Relay Relays." No. of attorney's file PC25020 ), filed December 4, 2003. Drug release rate The term "drug release rate" as used herein means the profile or curve that is obtained representing the amount of drug released from the drug. a sample of multiparticulates as a function of time after introduction in an aqueous use environment. The multiparticulates of the present invention can be designed for immediate release, controlled release, delayed release or any combination thereof or for displaying release profiles between these three types of release. Generally, the rate of drug release from a multiparticulate will depend on several factors, including the composition of the multiparticulate, the diameter of the multiparticulate and the pH of the environment of use. For some controlled release formulations, the rate of drug release from the multiparticulates can be characterized by a first order dissolution rate k constant. This dissolution rate constant can be determined by adjusting a graph of the amount of drug released from a sample as a function of time to the following first-order equation I: At = A- - [1-e-wl (l) Where At is the percentage of drug released from the multiparticulates at time t, A »is the percentage of drug released from the multiparticulates over extended periods of time, generally in more than three hours, t is the elapsed time of dissolution of the drug in minutes, and k is the rate constant of drug dissolution in min. "1 For some delayed-release formulations, the rate of release of the drug can be characterized by two parameters: (1) a "delay time" which is defined as the time between the introduction of the multiparticulate in the environment of use and the time in which the drug begins to be released to from the multiparticulate, and (2) a first-order dissolution rate constant that describes the rate of drug release after the delay time. In this case, the dissolution rate constant can be determined by adjusting a graph of the amount of drug released from a sample as a function of time to the following equation II of the first order of delayed release: At = A "• [1 - e "k (t" t)] (II) Where T is the delay time in minutes, and the other symbols are as defined in Equation I. Other equations known in the art may also be used to describe the velocity of drug release from multiparticulates. Such equations often require adjustment of the data so that one or more constants describing the rate of drug release can be determined.

The rate of drug dissolution from a multiparticulate can also be characterized by the amount released in a specified time after the introduction of the multiparticulate in an environment of use. The specified time can be selected as appropriate to determine the rate of drug release from the multiparticulate. Typically, times such as 30 minutes or 60 minutes are selected to determine the amount released from the multiparticulate. To determine the amount released, the multiparticulates are introduced into an aqueous use environment and the environment of use is sampled at the selected time and analyzed to determine the amount of drug released to the solution by analytical methods known in the art, such as analysis by high performance liquid chromatography (HPLC). The amount released can be expressed in terms of the mass of drug released, the fraction or percentage of drug initially present in the released multiparticulate, or some other convenient measurement of the amount of drug released. The rate of dissolution of the drug from a multiparticulate can also be characterized by the time necessary for half of the drug to be released from the multiparticulates after introduction into an environment of use. This value t? 2 can be determined by measuring the amount of drug released as a function of time upon introduction to an aqueous use environment using methods known in the art. As indicated above, the aqueous use environment may be in vivo fluids, such as the Gl tube of an animal such as a human, or may be more conveniently an in vitro testing medium, such as a buffer solution. Appropriate experimental solutions include aqueous solutions at 37 ° C which comprise (1) 0.1 N HCl, which simulates gastric fluid without enzymes; (2) 0.01 N HCl, which simulates gastric fluid that prevents excessive acid degradation by acid-sensitive drugs, and (3) 50 mM KH2PO4, adjusted to pH 6.8 using KOH or 50mM a3PO4, adjusted to pH 6 , 8 using NaOH, which both simulate intestinal fluid without enzymes. The inventors have also found that for some formulations, an in vitro experimental solution comprising 100 mM Na2HP? 4, adjusted to pH 6.0 using NaOH provides a discriminating means to differentiate between different formulations based on the dissolution profile. It has been determined that in vitro dissolution tests in such solutions provide a good indicator of behavior and bioavailability in vivo. This document describes additional details of in vitro tests and experimental solutions. A typical test for determining the release rate of the drug from the multiparticulates of the present invention can be carried out in the following manner. Samples of the multiparticulates are introduced into a Dissoette Type 2 flask according to the USP provided with Teflon-coated vanes rotating at 50 rpm. The flask contains 750 ml of IT solution maintained at 37.0 ° C ± 0.5 ° C. The multiparticulates are pre-moistened with 10 ml of the IT solution before being added to the flask. Then, in each time interval, a 3 ml sample of the fluid in the flask is collected. The collected sample is filtered using a 0.45 μm syringe filter before analyzing it by HPLC. The percentage of drug released from the multiparticulates at the time the sample was collected is then determined by dividing the drug mass in the dissolution flask (determined by multiplying the concentration determined by HPLC by the volume of the dissolution medium) between the total mass of drug that is initially added to the dissolution medium.

For example, 3 g of multiparticulates containing 50% by weight of the drug azithromycin can be added to 750 ml of IT solution. Thus, initially 3 g x 0 were added, 50 or 1.5 g of azithromycin to the solution. After 60 minutes, a sample of the solution can be taken and analyzed by HPLC and found to contain 1.0 mg / ml azithromycin. Thus, at t = 60 minutes, the amount of azithromycin released from the multiparticulates was 750 mg or 0.75 g (1 mg / ml x 750 ml). Therefore, the percentage of azithromylate released from the multiparticulates at t = 60 minutes is 100 x (0.75 g released * 1.5 g initially present), or 50%. The value of A »in equation I can be determined by performing a dissolution test as described above and controlling the amount of drug released from the multiparticulates as a function of time until no changes are observed in the amount of drug released. A »therefore represents the maximum amount of drug that can be released from the multiparticulate. Since the time needed to determine A ™ will vary depending on the composition of the multiparticulate, it is often more convenient to estimate A »by first measuring the amount of drug released from the multiparticulates after a convenient and sufficiently long time, such as 180 minutes (obtaining A? 8o), then collecting the multiparticulates from the dissolution flask and introducing them into a recovery solution to determine the residual amount of drug remaining in the multiparticulates (Ares¡duai) - A »is therefore equal to the sum of A? _o and Aresidual. A method for measuring Aresduai is to collect the multiparticulates after 180 minutes in an experimental medium, rinse them, and then introduce them in a recovery solution for the drug and ultrasonic for 30 minutes. An appropriate recovery solution will vary from one drug to another, but will typically comprise any of methanol, ethanol, isopropanol, acetonitrile (ACN), and mixtures thereof and mixtures thereof with water. Alternatively, an in vitro test known as a gastric buffer transfer test to intestinal buffer (TG-TI transfer test) can be used to simulate an aqueous use environment in vivo. In this test, samples of the multiparticulates are first introduced into an appropriate TG solution, such as the one described above. After a predetermined period of time, generally tfra t2Cr minutes, a concentrated buffer solution is added to the TG solution, increasing the pH of the solution so that it effectively becomes a simulated IT solution. The amount of drug released from the multiparticulates can then be determined using the procedures described above. Pharmaceutical forms Multiparticulates are susceptible to use in pharmaceutical forms with adjustable doses according to the weight of an individual animal that needs treatment simply by adjusting the mass of the particles of the dosage form according to the weight of the animal. They allow the incorporation of a large amount of drug into a simple pharmaceutical form such as a sachet which can be formulated in suspension which can be easily consumed orally. The multiparticulates can be mixed or combined with one or more pharmaceutically acceptable materials forming an acceptable pharmaceutical form. Acceptable pharmaceutical forms include tablets, capsules, sachets, oral powders for reconstitution, and the like. The invention also provides a method for treating a disease or condition susceptible to treatment with a therapeutic drug administered in a multiparticulate pharmaceutical form, comprising administering to an animal, including a human being, in need of such treatment, a pharmaceutically form of the type that is describes in the present document, the pharmaceutical form containing an effective amount of the drug. The amount of drug that is necessarily administered will vary according to well-known principles in the art, taking into account factors such as the severity of the disease or condition being treated and the size and age of the patient. In general, the drug should be administered so that an effective dose is received, the effective dose being determined between the safe and effective administration ranges already known for the drug of interest. Other features and embodiments of the invention will be obvious from the following examples, which are provided as an illustration of the invention, and not to limit its intended scope. EXAMPLES Twelve lots of multiparticulates containing drugs (MP1-MP12) were prepared by various procedures and then subjected to further treatment according to the invention to improve their stability.

MP1 Multiparticulates Multiparticulates comprising 50% by weight of azithromycin dihydrate were prepared in a 46% by weight vehicle of glyceryl monobehenates, dibenates and tribenates (commercially available as COMPRITOL 888 ATO from Gattefossé Corporation of Paramus, New Jersey) and 4% by weight. weight of poloxamer 407 (from a block copolymer of ethylene and propylene oxides commercially available as PLURONIC F127 or LUTROL F127 from BASF Corporation of Mt. Olive, New Jersey) using the following procedure; A mixture of 2.5 kg of azithromycin dihydrate, 2.3 kg of COMPRITOL 888 ATO and 0.2 kg of PLURONIC F127 were combined in a V-blender for 20 minutes. The lumps were then removed from this mixture using a Fitzpatrick M5A grinder at 3000 rpm, with the blades forward using a 0.065 inch (0.16 cm) screen. The mixture was then reintroduced into a V-mixer for a further 20 minutes. Then, three batches of this mixed material were combined to form a premix feed. The premix feed was delivered to a B & P 19mm twin screw extruder (MP19-TC with an L / D ratio of 25 purchased from B &P Process Equipment and Systems, LLC, Saginaw, MI) at a speed of 140 g / min. The extruder was set so that a molten feed suspension of the azithromycin dihydrate was produced in the vehicle at a temperature of about 90 ° C. The feed suspension was then administered to the center of a rotary disk atomizer. The rotating disk atomizer, which was made to measure, consisted of a bowl-shaped stainless steel disk 10.1 cm (4 inches) in diameter. The disc surface is heated with a thin film heater below the disc to approximately 88-90 ° C. That disk is mounted on an engine that drives the disk up to approximately 10,000 RPM. The complete assembly is included in a plastic bag approximately 8 feet (243.84 cm) in diameter to allow freezing and capture of the multiparticulates formed by the atomizer. Air is introduced from an opening below the disk providing cooling to the multiparticulates after freezing and to inflate the bag to its extended size and shape. A suitable commercial equivalent to this rotary disk atomizer is the 100mm FX1 rotary atomizer manufactured by Niro A / S (Soeborg, Denmark). The surface of the rotating disc atomizer was maintained from 88 to 90 ° C, and the disc rotated at 5500 rpm, during the formation of the multiparticulates of azithromycin. The maximum residence time of the azithromycin in the twin screw extruder was approximately 60 seconds, and the total time during which the azithromycin was exposed to the molten suspension was less than about three minutes. The average particle size of the resulting multiparticulates was determined to be 210 μm using an Horiba LA-910 particle size analyzer. The melting point of the vehicle, measured by DSC analysis was approximately 70 ° C. Multiparticulates MP2 Multiparticulates were formed as described for Multiparticulates M1, but a unique mixture of 3 kg of azithromycin dihydrate, 2.76 kg of COMPRITOL 888 ATO, and 0.24 kg of PLURONIC F127 was used to form the premix feed . The resulting multiparticulates had an average particle size of 200 μm and 77% ± 11% of the azithromycin in the multiparticulates was crystalline dihydrate. The melting point of the vehicle, as measured by DSC analysis, was approximately 70 ° C. Multiparticulate MP3 Multiparticulates were prepared comprising 50.53% by weight of azithromycin dihydrate, 45.47% by weight of COMPRITOL 888 ATO, and 4.0% by weight of PLURONIC F127 using the following procedure. A mixture of 4.04 kg of azithromycin dihydrate, 3.64 kg of COMPRITOL 888 ATO and 0, 32 kg of PLURONIC F127 was combined in a V-blender for 20 minutes. Then the lumps of this mixture were removed using a Fitzpatrick M5A grinder at 3000 rpm with the blades forward using a 0.065 inch (0.16 cm) screen. The mixture was then reintroduced into a V-mixer for a further 20 minutes to form a premix feed. The premix feed was delivered to a Leistritz 27 mm twin screw extruder (Model ZSE 27, American Leistritz Extruder Corporation, Somerville, NJ) at a rate of approximately 140 g / min. The extruder was fixed such that a molten feed suspension of the azithromycin dihydrate was produced in the COMPRITOL 888 ATO / PLURONIC F127 vehicle at a temperature of about 90 ° C. The feed suspension was then administered to the rotary disk atomizer which was used to form the Multiparticulates MP1. The surface of the rotating disk atomizer was maintained at 90 ° C and the disk rotated at 5500 rpm. The resulting multiparticulates had an average particle size of 210 μm and 78% ± 3% of the azithromycin in the multiparticulates was crystalline dihydrate. The melting point of the vehicle, as measured by DSC analysis, was approximately 70 ° C. Multiparticulates MP4 Multiparticulates were prepared as described for MP1 Multiparticulates but a unique mixture of 2.5 kg of azithromycin dihydrate, 2.3 kg of COMPRITOL 888 ATO and 0.2 kg of PLURONIC F127 was used to form the premix feed , the extruder was set so as to produce a molten feed suspension of azithromycin dihydrate in COMPRITOL 888 ATO / PLURONIC F127 at a temperature of about 85 ° C, and the rotating disk atomizer was maintained at 85 ° C. The resulting multiparticulates had an average particle size of 202 μm and 72% ± 5% of the azithromycin in the multiparticulates was crystalline dihydrate. The melting point of the vehicle, as measured by DSC analysis, was approximately 70 ° C. Multiparticulate MP5 Multiparticulates were prepared as described for MP3 Multiparticulates, but the premix feed comprised 50% by weight of azithromycin dihydrate, 45% by weight of COMPRITOL 888 ATO and 5% by weight of PLURONIC F127. The resultant multiparticulates had an average particle size of 205 μm and 84% ± 4% of the vehicle azithromycin was crystalline dihydrate. The melting point of the vehicle, as measured by DSC analysis, was approximately 70 ° C. Multiparticulate MP6 Multiparticulates were prepared as described for the MP3 multiparticulates, but the premix feed comprised 50.53% by weight of azithromycin dihydrate, 45.47% by weight of COMPRITOL 888 ATO and 4% by weight of PLURONIC F127 and the disk temperature was maintained from 88 to 89 ° C . The resulting multiparticulates had a mean particle size of 185 μm and 64% ± 3% of the azithromycin in the multiparticulates of vehicle was crystalline dihydrate. The melting point of the vehicle, as measured by DSC analysis, was approximately 70 ° C. Multiparticulates MP7 Multiparticulates were prepared comprising 50% by weight of azithromycin dihydrate, 45% by weight of COMPRITOL 888 ATO, and 5% by weight of PLURONIC F127 as described for MP Multiparticulates with the indicated exceptions. First, 112.5 g of COMPRITOL 888 ATO, 12.5 g of PLURONIC F127 and 2 g of water were added to a jacketed and sealed stainless steel tank equipped with a mechanical mixing paddle. Heating fluid was circulated at 97 ° C through the tank jacket. After about 40 minutes, the mixture had melted, with a temperature of about 95 ° C. This mixture was then mixed at 370 rpm for 15 minutes. Then, 125 g of azithromycin dihydrate that had been preheated to 95 ° C and 100% RH were added to the melt and mixed at a speed of 370 rpm for 5 minutes, producing a feed suspension of the azithromycin dihydrate in the melted components . The feed suspension was then pumped at a rate of 250 g / minute, using a gear pump, to the center of a rotating disk atomizer heated to 100 ° C and rotating at 7500 rpm. The particles formed by the rotating disk atomizer were frozen to ambient air and a total of 205 g of multiparticulates were collected. The average particle size was determined to be 170 μm using a Horiba LA-910 particle size analyzer. Samples of the multiparticulates were also evaluated by PXRD, which showed that 83% ± 10% of the azithromycin in the multiparticulates was crystalline dihydrate. The melting point of the vehicle, as measured by DSC analysis, was approximately 70 ° C. Multiparticulates MP8 Multiparticulates were prepared comprising 50% by weight of azithromycin dihydrate, 40% by weight of COMPRITOL 888 ATO and 10% by weight of PLURONIC F127 as described for Multiparticulates MP1, but 3 kg of pre-mix feed were fed to the extruder Samples of the multiparticulates were evaluated by PXRD and 85% ± 6% of the azithromycin in the multiparticulates was crystalline dihydrate. The melting point of the vehicle, as measured by DSC analysis, was approximately 70 ° C.

Multiparticulates MP9 Multiparticulates comprising 50% by weight of azithromycin dihydrate, 46% by weight of COMPRITOL 888 ATO and 4% by weight of PLURONIC F127 were prepared as described for Multiparticulates MP1 but the temperature of the feed suspension was 85 ° C and the rotating disk atomizer surface was maintained at 85 ° C. Samples of the multiparticulates were evaluated by PXRD and 82% ± 6% of the azithromycin in the multiparticulates was crystalline dihydrate. The melting point of the vehicle, as measured by DSC analysis, was approximately 70 ° C. MP10 Multiparticulates Multiparticulates were prepared comprising 50% by weight of azithromycin dihydrate, 47% by weight of COMPRITOL 888 ATO and 3% by weight of PLURONIC F127 as described for MP1 Multiparticulates, but the disc temperature was 86 ° C , the batch size 1015 g, and the speed of the feed stream was 180 g / minute. In addition, 3.45% by weight of water was added to the premix feed fed to the extruder. Samples of the multiparticulates thus formed by PXRD were evaluated and 94% ± 6% of the azithromycin in the multiparticulates was crystalline dihydrate. The melting point of the vehicle, as measured by DSC analysis, was approximately 70 ° C. Multiparticulates MP11 Multiparticulates were prepared comprising 50% by weight of azithromycin dihydrate, 47% by weight of COMPRITOL 888 ATO, and 3% by weight of PLURONIC F127 as a dissolution enhancer. The melting point of the vehicle, determined by DSC analysis, was approximately 70 ° C. First, 15 kg of azithromycin dihydrate, 14.1 kg of COMPRITOL 888 ATO and 0.9 kg of PLURONIC F127 were weighed and passed through a Quadro 194S Comil grinder in that order. The speed of the mill was set at 600 rpm. The grinder was provided with a No. 2C-075-H050 / 60 screen (first special row), a flat paddle impeller No. 2C-1607-049, and a 0.25 cm (0.255 inch) spacer between the impeller and the sieve. The mixture was combined using a 100 I stainless steel beaker Servo-Lift mixer rotating at 20 rpm, for a total of 500 rotations, forming a pre-mix feed. The premix feed was administered to a 50 mm twin screw extruder (Model ZSE 50, American Leistritz Extruder Corporation, Somerville, NJ) at a rate of 25 kg / h. The extruder operated in cogratory mode at approximately 300 rpm, and was interfaced with a melt / spray freeze unit. The extruder had nine segments of segmented drums and a total extruder length of 36 screw diameters (1.8 m). Water was injected into drum number 4 at a rate of 8.3 g / minute. The extrusion rate of the extruder was set such that it produced a molten feed suspension of the azithromycin dihydrate in COMPRITOL 888 ATO / PLURONIC F127 at a temperature of about 90 ° C. The molten feed suspension was then administered to the rotary disk atomizer described in relation to MP1 Multiparticulates, maintained at 90 ° C and rotating at 7600 rpm. The maximum total time during which the azithromycin was exposed to the molten suspension was less than about 10 minutes. The particles formed by the rotating disk atomizer were cooled and frozen in the presence of cold air circulating in the product collection chamber. The average particle size was determined to be 188 μm using a Horiba LA-910 particle size analyzer. Samples of the multiparticulates were also evaluated by PXRD, which showed that approximately 99% of the azithromycin in the multiparticulates was in the dihydrated crystalline form. MP12 Multiparticulates Multiparticulates were prepared comprising 50% by weight of azithromycin dihydrate, 47% by weight of COMPRITOL 888 ATO, and 3% by weight of LUTROL F127 using the following procedure. First, 140 kg of azithromycin dihydrate were weighed and passed through a Quadro Comil 196S mill with a mill speed of 900 rpm. The grinder was provided with a sieve n ° 2C-075-H050 / 60 (first special row, 0.19 cm (0.075")), an impeller No. 2F-1607-254, and a spacer of 0.57 cm (0.225 inches) between the impeller and the screen, then 8.4 kg of the LUTROL F127 and then 131.6 kg of the COMPRITOL 888 ATO were weighed and passed through a Quadro 194S Comil grinder. The grinder was fitted with a n ° 2C-075-R03751 (0.19 cm (0.075")) screen, an impeller n ° 2C-1601-001, and a 0.57 cm (0.255 inch) spacer ) between the impeller and the screen. The mixture was combined using a Gallay mixer of 1.07 m3 (38 cubic feet) of stainless steel, rotating at 10 rpm for 40 minutes, for a total of 400 rotations, forming a pre-mix feed. The premix feed was administered to a Leistritz 50 mm twin screw extruder (Model ZSE 50. American Leistritz Extruder Corporation, Somerville, NJ) at a rate of approximately 20 kg / hr. The extruder operated in co-rotary mode at approximately 100 rpm, and was in interface with a melt / spray freeze unit. The extruder had five zones of segmented drums and a total extruder length of 20 screw diameters (1.0 m). Water was injected into drum number 2 at a rate of 6.7 g / min (2% by weight). The extrusion rate of the extruder was set such that it produced a molten feed suspension of the azithromycin dihydrate in COMPRITOL 888 ATO / LUTROL F127 at a temperature of about 90 ° C. The feed suspension was then administered to the rotary disk atomizer which is described in connection with the Multiparticulates MP1, which rotated at 6400 rpm and maintained at a temperature of approximately 90 ° C. The maximum total time during which the azithromycin was exposed to the molten suspension was less than 10 minutes. The particles formed by the rotating disk atomizer were cooled and frozen in the presence of cold air circulating in the product collection chamber. The average particle size was determined to be approximately 200 μm using a Malvern particle size analyzer. Samples of the multiparticulates were also evaluated by PXRD, which showed that approximately 81% of the azithromycin in the multiparticulates was in the dihydrated crystalline form. The drug release rates for the Multiparticulates MP1-MP12 were then determined both in intestinal buffer (TI) and in gastric buffer (TG) as indicated below. Drug release rate in IT In the following examples, the rate of drug release from the multiparticulates in a simulated IT solution was determined using the following procedure. A sample of 750 mg of the multiparticulates was introduced into a Dissoette Type 2 flask according to the USP provided with Teflon-coated vanes rotating at 50 rpm. The flask contained 750 ml of IT solution consisting of Na 3 PO 40.05 M adjusted to pH 6.8 with NaOH maintained at 37.0 ° C ± 0.5 ° C. The multiparticulates were pre-wetted with 10 ml of the simulated intestinal buffer solution before being added to the flask. A 3 ml sample of the fluid was then collected in the flask at various times after the addition of the multiparticulates to the flask. Samples were filtered using a 0.45 μm syringe filter before analyzing by HPLC. (Hewlett Packard 1100, Waters Symmetry Ce column, acetonitrile: methanol: 25 mM KH2PO4 buffer 45:30:25 at 1.0 ml / minute, the absorbance was measured at 210 nm with a photodiode device spectrophotometer). The multiparticulates were then removed from the dissolution flask and introduced into a recovery solution consisting of 100 ml of acetonitrile (ACN) to which 100 ml of water was added. This solution was sonicated for 30 minutes, after which the samples were collected, filtered, using a syringe filter and then analyzed by HPLC as described above obtaining the amount of residual azithromycin remaining in the multiparticulates . The dissolution rate constant of the drug in TI was determined by fitting the data to the following equation: At = A "• [1 - e * | where At is the percentage of drug released from the multiparticulates at time t, A »is the percentage of drug released from the multiparticulates over prolonged periods of time, equal in this case to the amount released at the end of the dissolution test plus the residual amount in the multiparticulates, t is the time in minutes, and k is the rate constant of dissolution of the drug in min "1. Rate of release of the drug in TG The rate of drug release from the multiparticulates in a simulated TG solution was determined as described above, but the TG dissolution medium consisted of 750 ml of 0.01 N HCl. Samples were collected at various time points after the addition of the multiparticulates to the flask and analyzed for To determine the drug, the residual drug remaining in the multiparticulates was determined and the dissolution rate constant in TG was calculated, as it was determined. previously described Example 1 Multiparticulates MP2 were subjected to further treatment in the following manner. Samples of the multiparticulates were introduced in a shallow pan at a depth of approximately 2 cm. This tray was then placed in a controlled atmosphere oven at 40 ° C and 75% RH for 5 days. The multiparticulates subjected to further treatment were analyzed by PXRD and 96% ± 11% of the azithromycin in the multiparticulates was determined to be in the dihydrated crystalline form. A) Yes, the subsequent treatment procedure produced a relative degree of improvement of the crystallinity of 5.8 ((1 - 0.77) + (1 - 0.96)). The dissolution rate of azithromycin from the multiparticulates subjected to further treatment was determined using a dissolution medium of TI, with the results presented in Table 1. The dissolution rate constant in TI was calculated and presented in Table 2. Samples of the multiparticulates subjected to further treatment of Example 1 were sealed in packs as described for Control C1 and placed in a controlled atmosphere oven set at 40 ° C / 75% RH for 18 hours. weeks The samples were then removed from the packages and the rate of azithromycin release was measured from the multiparticulates as described above. The results of these tests, which are presented in Tables 1 and 2, show that the dissolution rate constant for multiparticulates stored for 18 weeks at 40 ° C and 75% RH (0.017 min "1) was identical to that of the multiparticulates subjected to subsequent treatment before storage, thus, the change in the dissolution behavior was essentially null.

Table 1 Table 2 Example 2 The MP3 Multiparticulates were subjected to further treatment as described in Example 1 but the treatment was for 7 days. The rate of release of azithromycin from the multiparticulates thus subjected to further treatment was determined in TI, with the results presented in Table 3. The dissolution rate constant in IT was calculated from these data and presented in Table 4. Samples of the multiparticulates subjected to further treatment of Example 2 were sealed in packs such as Control C1 and placed in a controlled atmosphere oven set at 40 ° C / 75% RH for 3 weeks. The samples were then extracted from the packages and the release rate of azithromycin was measured from the multiparticulates as described above. The results of these tests, which are presented in Tables 3 and 4, show that the dissolution rate constant for the multiparticulates stored for 3 weeks at 40 ° C and 75% RH (0.016 min "1) was identical to the of the multiparticulates subjected to further treatment before storage, Thus, the change in dissolution rate was essentially zero.

Table 3 Example 2 Time (minutes) Azithromycin released Initial 0 0 5 6 15 18 30 36 60 58 120 85 180 95 After 3 weeks 0 0 5 6 15 19 30 37 60 59 Table 4 Example 3 The MP4 Multiparticulates were subjected to further treatment as described in Example 1 but the multiparticulates were subjected to further treatment for 2 days at 45 ° C / 60% RH. The multiparticulates subjected to further treatment were analyzed by PXRD and it was found that 98% ± 5% of the azithromycin of the multiparticulates was in the dihydrated crystalline form. Thus, the subsequent treatment procedure produced an increase in the percentage of drug crystallinity of the multiparticulates. The relative degree of improvement of the crystallinity was 14. The release rate of azithromycin from the multiparticulates thus subjected to further treatment was determined in TI, with the results presented in Table 5. The constant of dissolution rate in TI and is presented in Table 6. Samples of the multiparticulates subjected to further treatment of Example 3 were sealed in packs such as Control C1 and placed in a controlled atmosphere oven set at 40 ° C / 75 % RH for six weeks. The samples were then removed from the packages and the release rate of azithromycin was measured from the multiparticulates as described above. The results of these tests, which are presented in Tables 5 and 6, show that the dissolution rate constant for multiparticulates stored for 6 weeks at 40 ° C and 75% RH (0.016 min "1) was 89% of the dissolution rate constant of the multiparticulates subjected to further treatment before storage (0.018 min "1), producing a change in dissolution rate of 11%.

Table 5 Table 6 Example 4 The MP5 Multiparticulates were subjected to further treatment as described in Example 1. The multiparticulates subjected to further treatment were analyzed by PXRD and it was determined that 99 +% ± 4% of the azithromycin in the multiparticulates was in the crystalline form dihydrate. Thus, the subsequent treatment procedure produced an increase in the percentage of crystallinity of the drug, which corresponds to a relative degree of improvement of the crystallinity of at least 16. The rate of release of azithromycin from the multiparticulates subjected to further treatment is determined in TI, with the results presented in Table 7. The dissolution rate constant in TI was calculated and is presented in Table 8. Samples of the multiparticulates subjected to further treatment of Example 4 were sealed in packages such as in Control C1 and were introduced in a controlled atmosphere oven set at 40 ° C / 75% RH for three weeks. The samples were then extracted from the packages and the release rate of the azithromycin was measured from the multiparticles as described above. The results of these tests, which are presented in Tables 7 and 8, show that the dissolution rate constant for the multiparticulates stored for 3 weeks at 40 ° C and 75% RH (0.025 min "1) was identical to that of the multiparticulates subjected to Subsequent treatment before storage which results in a change in the essentially null dissolution behavior.

Table 8 Example 5 The MP6 Multiparticulates were subjected to further treatment as described in Example 1. The multiparticulates subjected to further treatment were analyzed by PXRD and it was found that 86% ± 3% of the azithromycin in the multiparticulates was in the dihydrated crystalline form . Thus, the subsequent treatment procedure produced an increase in the crystallinity of the drug in the multiparticulates, which corresponds to a relative degree of improvement of the crystallinity of 2.6. The release rate of azithromycin from the multiparticulates subjected to further treatment was determined in TI, with the results presented in Table 9. The dissolution rate constant in TI was calculated and is presented in Table 10. Samples of the multiparticulates subjected to further treatment of Example 5 were sealed in packages such as Control C1 and placed in a controlled atmosphere oven set at 40 ° C / 75% RH for 12 weeks. The samples were then removed from the packages and the release rate of azithromycin was measured from the multiparticulates as described above. The results of these tests, which are presented in Tables 9 and 10, show that the dissolution rate constant for multiparticulates stored for 12 weeks at 40 ° C and 75% RH (0.019 min'1) was 95% of the multiparticulates subjected to further treatment before storage (0.020 min'1), which results in a change in the dissolution behavior of 5%. Table 9 Table 10 Examples 6-15 The MP3 Multiparticulates were subjected to further treatment using the 10 sets of different conditions shown in Table 11 and the release rates of azithromycin were determined from the multiparticulates subjected to further treatment in TI. The dissolution rate constants in TI were then calculated and the results are summarized in Table 11. These data show that the lower the temperature of the subsequent treatment, the longer the subsequent treatment should be to obtain multiparticulates with a release rate. of stable azithromycin.

Table 11 Example 16 Multiparticulates MP1 were subjected to further treatment by introducing them into a controlled atmosphere chamber maintained at 47 ° C and 70% RH during the times shown in Table 12. The rate of release of azithromycin from the multiparticulates subjected to further treatment was determined in TI, and then the dissolution rate constants in TI were calculated for all time intervals except 4 and 8 hours. The results are summarized in Table 12.

Multiparticulates subjected to further treatment were also analyzed by PXRD to determine the crystallinity of azithromycin in the multiparticulates. These data, which are also shown in Table 12, indicate that the degree of crystallinity of azithromycin increased with the time of subsequent treatment, reaching 99 +% of the crystalline dihydrate after approximately 18 hours of subsequent treatment.

Table 12 SD = not determined Example 17 The MP1 Multiparticulates were subjected to further treatment by placing them in a tray at a depth of 10 cm, and then introducing the tray into a controlled atmosphere chamber maintained at room temperature. 47 ° C and 70% RH for 24 hours. After the subsequent treatment, samples were obtained from the multiparticulates subjected to further treatment of the upper, middle and lower part of the tray, which corresponds to depths of 0-2 cm, 4-6 cm, and 8-10 cm, respectively . The rate of release of azithromycin from the multiparticulates subjected to further treatment was then determined in TI, and the dissolution rate constants in TI were calculated. The results, summarized in Table 13, show that the behavior of the multiparticulates subjected to subsequent treatment was practically the same regardless of the depth of sampling.

Table 13 Examples 18-22 MP4 Multiparticulates were subjected to further treatment by introducing them into a controlled atmosphere chamber under the conditions shown in Table 14. The release rate of azithromycin from the multiparticulates subjected to further treatment was determined in TI. and dissolution rate constants were calculated. The results are summarized in Table 14. The multiparticulates subjected to further treatment were also analyzed by PXRD to determine the crystallinity of the azithromycin of the multiparticulates. These data, which are also shown in Table 14, indicate that the degree of crystallinity of the azithromycin dihydrate increased with the subsequent treatment time, reaching at least 97% in the subsequent treatment times studied. Thus, the subsequent treatment procedure produced a relative degree of crystallinity improvement of at least 9.3 for the conditions studied.

Table 14 NA = Not applicable Control C1 The dissolution stability of MP7 Multiparticulates was determined by sealing samples of the multiparticulates in conventional aluminum foil / polymer / aluminum foil packets and introducing them into a controlled atmosphere oven set at 40 ° C / 75 % RH for three weeks. The samples were extracted from the packages and the release rate of azithromycin was measured from the multiparticulates in TG as described above but data were also obtained at 120 minutes and 180 minutes. The results of this test are presented in Table 15. The dissolution rate constant in TG was then calculated as described above, and the results are reported in Table 16. The data shows that for the untreated MP7 Multiparticulates, the dissolution rate constant (0.074 min "1) after storage for three weeks at 40 ° C / 75% RH was almost 2.6 times the dissolution rate constant (0.028 min" 1) before storage, which translates into a change in dissolution behavior of 260% for multiparticulates not subjected to further treatment.

Table 15 Table 16 Example 23 MP10 Multiparticulates were subjected to further treatment by placing them in a tray at a depth of approximately 2 cm and the tray was placed in a controlled atmosphere oven at 40 ° C and 75% RH for 5 days. We analyzed samples of the multiparticulates subjected to further treatment by PXRD and 99+% ± 6% of the azithromycin in the multiparticulates was in the dihydrated crystalline form. Thus, the subsequent treatment procedure increased the crystallinity of the multiparticulate drug, which results in a relative degree of crystallinity improvement of at least 6 ([1 - 0.94] / [1 - 0.99]). The release rate of azithromycin from the multiparticulates subjected to further treatment of Example 23 was determined in TI and the results are reported in Table 17. The dissolution rate constant in TI was calculated and is reported in Table 18 .

Table 17 Samples of the multiparticulates subjected to further treatment of Example 23 were sealed in packages such as Control C1 and placed in a controlled atmosphere oven set at 40 ° C / 75% RH for 12 weeks. The samples were then removed from the packages and the release rate of azithromycin was measured from the multiparticulates as described above. The results are also reported in Table 17. These results show that the dissolution behavior of the multiparticulates subjected to subsequent treatment of Example 23 was practically the same after storage for 12 weeks than before storage, indicating that the treatment procedure later stabilized the dissolution behavior.

Table 18 Example 24 Multiparticulates MP11 were subjected to further treatment in the following manner. Samples of the multiparticulates were introduced into sealed drums. The drums were then placed in a controlled atmosphere chamber at 40 ° C for 3 weeks. The rate of release of azithromycin from these multiparticulates subjected to further treatment was determined using the following procedure. Approximately 4 g of the multiparticulates (containing about 2000 mgA of the drug) were placed in a 125 ml flask containing approximately 21 g of a delivery vehicle consisting of 93 wt% sucrose, 1.7 wt% trisodium phosphate, 1.2% by weight of magnesium hydroxide, 0.3% by weight of hydroxypropylcellulose, 0.3% by weight of xanthan gum, 0.5% by weight of colloidal silicon dioxide, 1.9% by weight weight of titanium dioxide, 0.7% by weight of cherry flavor, and 1.1% by weight of banana flavor. Then, 60 ml of purified water was added and the bottle was stirred for 30 seconds. The content was added to a Dissoette Type 2 flask according to the USP provided with Teflon-coated vanes rotating at 50 rpm. The flask contained 840 ml of 100 M Na2HPO4 buffer solution, at pH 6.0 maintained at 37.0 ° C ± 0.5 ° C. The bottle was rinsed twice with 20 ml of the flask buffer, and the rinse was returned to the flask providing a final volume of 900 ml. A 3 ml sample of the flask fluid was then collected at 15, 30, 60, 120, and 180 minutes after the addition of the multiparticulates to the flask. Samples were filtered using a 0.45 μm syringe filter before analyzing by HPLC (Hewlett Packard 1100, Waters Symmetry C8 column, acetonitrile: methanol: 25 mM KH2PO4 buffer 45:30:25 at 1.0 ml / minute , the absorbance was measured at 210 nm with a photodiode device spectrophotometer). The results of this dissolution test are reported in Table 19.

Table 19 Example 25 Multiparticulates MP12 were subjected to further treatment in the following manner. Before treatment, 81% by weight of the drug in the multiparticulates was in the dihydrated crystalline form. The multiparticulates contained water, a mobility enhancing agent, which had been injected into the extruder that was used to form the multiparticulates. Samples of the multiparticulates were introduced in sealed drums. The drums were then introduced into the controlled atmosphere chamber at 40 ° C for 10 days. Samples of the multiparticulates subjected to further treatment by PXRD were evaluated, which showed that after the subsequent treatment approximately 99% by weight of the azithromycin in the multiparticulates was in the dihydrated crystalline form. Thus, the use of an agent that enhances mobility during the formation of the multiparticulates together with a subsequent treatment at elevated temperature, produced a substantial increase in the crystallinity of azithromycin in the multiparticulate. The terms and expressions that have been used in the above description are used herein as terms of description and not of limitation, and there is no intention, in the use of such terms and expressions, to exclude equivalents of the characteristics that are described. show and describe or portions thereof, recognizing that the scope of the invention is defined and limited only by the following claims.

Claims (16)

1. A method for preparing multi-drug containing drugs comprising the steps: (a) forming multiparticulates comprising a drug, a pharmaceutically acceptable carrier, and an optional solution enhancer, said carrier having a melting point of Tm ° C; and (b) removing the multipathicsates of step (a) by at least one of (i) heating said multiparticulates to a temperature of at least about 35 ° C and less than about (Tm ° C -10 ° C), and ( I) exposing said multiparticulates to an agent that enhances mobility, forming a multiparticulate subject to subsequent discussion; wherein the step (b) is carried out for a sufficient period of time to achieve a degree of crystallinity of said drug in said multiparticulates which is greater than the crystallinity of said drug in a control composition essentially made up of the multiparified ones. brought from the country (a).

2. The method of claim 1, wherein step (b) comprises heating said multiparticulates as exposing said multiparticulates to said agent that enhances mobility.

3. The method of claim 1, wherein step (b) comprises heating said multiparticulates at a temperature of 40 ° to 50 ° C in an atmosphere of at least about 50% relative humidity for about 30 days or less.

4. A process for preparing multiparticulates containing drugs comprising the steps: (a) forming multiparticulates comprising a drug, a pharmaceutically acceptable carrier, and an optional solution enhancer; and (b) separating said multiparticulates from step (a) by exposing said multiparticulates to an agent that enhances mobility, forming a multiparticulate subjected to subsequent irradiation; wherein the efapa (b) is carried out for a period of time sufficient to achieve a degree of crisiality of said drug in said multiparticulates which is greater than the crystallinity of said drug in a control composition constituted essentially by the multiparticulates without deal with stage (a).

5. A method for preparing multiparticides containing drugs comprising the steps: (a) forming multiparticulates comprising a drug, a pharmaceutically acceptable carrier, said carrier having a melting point of Tm ° C, an optional solution potentiator, and an agent that enhances mobility; and (b) heating said multiparticulates to a temperature of at least about 35 ° C and less than about (Tm ° C -10 ° C) forming a multiparticulate subjected to further treatment; wherein the step (b) is carried out for a period of time sufficient to achieve a degree of crystallinity of said drug in said multiparticulates which is greater than the crystallinity of said drug in a conirol composition constituted essentially by the multiparticulates without fratar from stage (a).

6. The method of claim 5, wherein step (b) comprises the steps: (i) introducing said multiparticulates into a sealed container; and (ii) heating said sealed package to a temperature not higher than about (Tm-10 ° C) for a sufficient time to achieve a degree of crisyality of the drug of at least 95%.

7. The method of claim 5, wherein step (a) comprises the steps: (i) forming a premix feed comprising said drug, said vehicle and said agent that enhances mobility; (ii) forming a molten mixture of said premix feed in an extruder; (iii) administering said molten mixture to an atomization medium forming droplets of said mixture; and (iv) freezing said droplets forming said multiparticulates.

8. The method of claim 5, wherein step (a) comprises the steps: (i) forming in an extruder a first molten mixture comprising said drug and said vehicle; (ii) administering said agent that promotes mobility to said extruder forming a second molten mixture comprising said drug, said vehicle and said agent that promotes mobility; (iii) administering said second molten mixture to an atomization medium forming droplets; and (iv) freezing said droplets forming said multiparticulates.

9. The method of claim 8, wherein step (b) comprises the steps: (i) introducing said multipaths into a sealed package; and (ii) heating said sealed package to a temperature not exceeding about (Tm-10 ° C) for a sufficient time to achieve a degree of crispness of the drug of at least 95%.

10. The method of claim 9, wherein said sealed package is heated to a temperature of 40 ° to 50 ° C for about 5 to about 21 days.

11. The method of any of claims 1-10, wherein said mobility enhancing agent is selected from the group consisting of water, methanol, ethanol, propanol and its isomers, butanol and its isomers, acetone, methyl ethyl ketone, methyl isobutyl ketone, acetate of ethyl, tetrahydrofuran, acetonitrile, cyclohexane, formic acid, acetic acid, and mixtures thereof.

12. The method of claim 11, wherein said drug is azithromycin dihydrafada, said agent that enhances mobility is water, and wherein said water is in a form that is selected from a liquid and a vapor.

13. The method of claim 12, wherein said mobility enhancing agent is water in the form of water vapor comprising more than about 10% relative humidity.

14. The product of the method of any of claims 1-10, wherein said drug is azithromycin.

15. The product of claim 14, wherein said drug is azithromycin dihydrate, said carrier comprises a glyceride having at least one alkylate substituent of at least 16 carbon atoms and said dissolution enhancer is a poloxamer.

16. The product of claim 15, wherein the azithromycin dihydraphase is present in a quantity from about 35 to about 55% by weight, said glyceride is present in an amount of from about 40 to about 65% by weight and said poloxamer is present in an amount from about 0.1 to about 15% by weight.