MXPA00008314A - Stable shaped particles of crystalline organic compounds - Google Patents

Abstract

The present invention provides storage stable, shaped particles of allotropic organic compounds. The particles of the present invention can be shaped according to the desired application. Preferred shapes of such particles are microspheres, particularly those having diameters of about 1 to about 1,000 microns. The stable shaped particles of the present invention are particularly well-suited to the fabrication of pharmaceutical formulations, particularly where sustained release and uniform bioavailability are desired. The storage stable particles are formed by a solid state crystallization of allotropic organic compounds. The solid state crystallization process of the present invention affords a means for achieving a storage stable crystalline form of said allotropic compound without loss or deterioration of the original particle dimensions.

Description

STABLE CONFIGURED PARTICLES OF CRYSTAL ORGANIC COMPOUNDS BACKGROUND OF THE INVENTION It is well known that many substances are prone to crystallize in different forms, depending on the conditions under which they crystallize. Different crystalline structures resulting from the crystallization of a particular substance are termed polymorphs or pseudopolymorphs. It is also known that, when they melt and cool rapidly below their melting point, that is, they freeze under melting, the atoms or molecules that make up most substances need some time to be arranged in the most natural order for the environment where they are placed. Therefore, they remain in unstable amorphous or semi-amorphous states or are organized into metastable polymorphs.

Metastable polymorphs can be enantiotropic, which is a property of certain substances that means they exist in more than one crystal form (Girón, Thermal Analysis and Calorimeter Method in the Characterization of Polymorphs and Solvates, Thermochimica Acta, 248 (1995) 1 -59; Parker, Dictionary of Scientific and Technical Terms, McGraw Hill, Inc., 1984, 541; Hancock et al., Characteristics and Significance of the Amorphous State in Pharmaceutical Systems, J. Pharm. Sci., Vol. 86, No. 1, 1997, 1-12 In general, there is a variation between the various crystal forms or facies of an enantiotropic substance so that one form is stable above the transition point temperature and the other is stable below Consequently, the habit of a crystalline mineral is dynamic and reversible depending on the environmental conditions, metastable polymorphs usually transform over time into structures more This process of natural crystallization is called "aging", and it happens over time without the intervention of the human being. This process of natural "aging" is usually long-lasting and unpredictable, and, therefore, is very expensive and potentially dangerous, particularly in the manufacture of pharmaceutical products. The unpredictable nature arises since the aging process greatly depends on environmental factors. Yu, "Inferring Thermodynamic Stability Relationship of Polymorphs from Melting Data", J. Pharm. Sci., Vol. 84, No. 8, 966-974 (1995). However, stable, crystallized substances are generally required for optimal and reliable bioactivity and bioavailability. If the metastable particles, for example, microspheres or pellets, are placed in an aqueous medium before full crystallization occurs, the deformation of the particle shape or even the complete destruction of the particles can occur in a matter of hours. In addition, different polymorphs of a particular substance will have different dissolution rates, resulting in lack of stability and loss of uniformity between different batches of the same drug. For example, Haleblian and others report differences in dissolution rates between polymorphs of fluprednisolone. Haleblian et al., "Isolation and Characterization of Some Solid Phases of Fluorprednisolone", J. Pharm. Sci. Vol. 60, No. 10, 1485-1488 (1971). For pharmaceutical applications, it is particularly important to obtain stable crystallization, since the administration of a therapeutic compound usually requires suspension in an aqueous solution suitable for injection. Also, even if the first compound is not suspended in an aqueous medium, when it is administered to the patient it is subjected to biological fluids that are water-based. The same is true for pellets and implants that are placed in the body through a surgical procedure or other procedure. To ensure the physical integrity of the shaped particles and uniform release of the active agent, it is necessary to ensure complete crystallization before administration. Some workers have tried to improve the stability of therapeutic compounds by inducing crystallization. For example, Matsuda et al. Suggest modifying crystalline structures using a temperature controlled dispersion drying method. Matsuda et al., "Physicochemical Characterization of Sprayed-Dried Phenylbutazone Polymorphs", J. Pharm. Sci., Vol. 73, No. 2, 73-179 (1984).

However, since the dissolution of a solid is also related to surface erosion, the shape and size of the therapeutic particles should also be considered in addition to the solubility. Carstensen, "Pharmaceutical Principles of Solids and Solid Dosage Forms," Wiley Interscience, 63-65, (1977). In this way, when a pharmaceutical compound is administered as a solid or suspension, the conservation of the particular shape and size becomes an important factor to ensure the control and reproducibility of bioavailability and biodynamics. With this in mind, Kawashima and others proposed a method of spherical crystallization of Tranilast through the use of two mutually insoluble solvents, and the conversion of the resulting polymorphs through heat. Rawashima et al., "Characterization of Polymorphs of Tranilast Anhydrate and Tranilast Monohydrate when Crystallized by Two Solvent Change Spherical Crystallization Techniques" in J. Pharm. Sci., Vol. 80, No. 5, 472-477 (1981). It has also been reported that the natural aging process can be accelerated through heating. Ibrahim et al., "Polymorphism of Phenylbutazone: Properties and 66, No. 5, 669-673 (1977); Hancock et al., Characteristics and Significance of the Amorphous State in Pharmaceutical Systems, J. Pharm. Sci., Vol. No. 1, 1-12 (1977) In some cases, however, the required heat is such that the integrity or form of the substance is compromised.In several cases where heat has been used, the reproduction of results, stability and therefore control of the size of the crystal within the particle has been difficult or even impossible to have.In addition, in some cases, the most stable polymorph of a particular substance is a hydrate, making it impossible for it to reach the desired polymorph at In addition, heating is rarely suitable for stable crystallization in the case of mixtures, thus heat processing as a method to obtain stable polymorphs, although superior to the process of aging. has important limitations. Other workers have studied the use of solvent vapors to induce the crystallization of polymeric species. Such efforts include putative crystallization and change of the mechanical properties of polymeric compounds, as described in the patent of US Pat. No. 4,897,307. Also see, Miller, A. J. et al., "Melting behavior, mechanical properties and fracture of crystallized polycarbonates" in Latin American Metallurgy and Materials, 5 (2), 130-141 (1985); and Tang, F. et al., "Effect of Solvent Vapor on Optical Properties of Pr / sub 4VOPe in polymethylmethacrylates", in Journal of Applied Physics, 78 (10), 5884-7 (1995). Tang et al. Used vapors of organic solvent to transform a polymer matrix, dye Pr4VOPc (vanadyl phthalocyanine having 4 propyl substituents) from vitreous phase I to crystallized phase II. Müller and Paredes describe the crystallization of polycarbonate polymers in terms of the incorporation of solvents or plasticizers in the amorphous state. For the knowledge of the inventors of the present, said aspect has not been used to form stable crystals of organic compounds frozen by fusion and mixtures.

COMPENDIUM OF THE INVENTION The present invention provides stable, reproducible particles of crystalline organic compounds. The stable particles of crystalline organic compounds of the present invention may be homogeneous particles of a single organic compound, or may be mixtures of two or more organic compounds. The stable particles of the present invention retain a constant shape and size during prolonged storage, such as in an aqueous suspension. Said stable particles can be manufactured with a uniform size and shape, and will retain said size and shape despite long-term storage.; and in this way, they are particularly advantageous in pharmaceutical formulations. The present invention further provides a method for obtaining said stable particles, capable of reproduction. The method involves exposing the above shaped particles, wherein one or more organic compounds are in a crystalline, amorphous or metastable form, to an atmosphere saturated with solvent vapors. The solvents are composed of one or more liquids wherein at least one or more organic compounds are soluble. The method of the present invention offers several advantages. It is applicable to substances in which the most stable polymorph is a hydrate, since it does not release the water molecules and thus allows the incorporation of water molecules into the crystal lattice during formation. It is applicable to heat-labile substances, since high temperatures are avoided. And it allows the formation of a stable structure that involves a mixture of substances, which, with the exception of the eutectic mixture composition, can not be obtained through heat. More particularly, the present invention involves a method for crystallizing or recrystallizing an amorphous or metastable crystalline organic compound or mixture. The method comprises the steps of, (i) exposing the compound or mixture to an atmosphere saturated with the vapors of one or more liquids, at least one of which must be a solvent for said compound or mixture, for a sufficient time to transforming the metastable compound or mixture into a stable, crystallized compound or mixture; and (ii) recovering the crystallized compound or mixture, stable for storage or use. The method can be performed using any enclosure, where the volume, temperature and atmospheric content and pressure can be manipulated. The chamber is capable of containing an atmosphere saturated with the desired solvent vapors. The saturation point is reached when the vapors fill the chamber without causing condensation on the surfaces of the chamber or particles. Preferably, the particles are formed into a shaped particle, such as a microsphere, pellet or implant form. The shaped particles having a uniform surface area and capable of reproduction are especially preferred. This can be effected through freezing by fusion. In addition, the shaped particles are preferably configured to a uniform particle size or size scales. Up to this point, the methods described in the patents of US Pat. No. 5,633,014, 5,643,604, and 5,360,616 can be used, which are incorporated herein by reference. Alternatively, any suitable method that results in a metastable crystalline conglomeration can be used. When the method involves crystallization of a mixture, the mixture can be eutectic or non-eutectic. The particles are placed in the chamber or other suitable enclosure using any suitable means so that they are exposed to solvent vapors, but do not immerse in or otherwise make contact with the liquid solvent. The particles are fixed or moving inside the chamber. The period of time necessary to effect crystallization according to the method herein will vary depending on various physicochemical properties consistent with established principles. For example, the optimal exposure time will vary depending on the particle size and shape, the chemical composition of the particle, the shape of the solid state of the particle (ie, amorphous, metastable crystalline), the type and concentration of solvent used. , and the treatment temperature. Generally, a scale of several seconds to 48 hours is applied, or most preferably from 1 to 36 hours. Partial partial crystallization of particles does not seem to modify these time scales. The optimization of the exposure time will vary depending on the solvent system used, the organic compound (s) to be crystallized, and other variables, and is within the experience of one skilled in the art. As shown below, a 24-hour exposure time will be commonly effective. An advantage of the present invention is that it is applicable to heat-labile substances since high temperatures can be avoided. In this way, the applicable temperature scale is broadly defined and depends on the particular compound. Generally, the temperature of the vapor atmosphere is sufficient to obtain the vaporization of the solvent, but below the melting point of the particles. The solvent or solvents used in the method of the present invention can be any agent classified as a solvent for the organic compound (s) of interest. As will be appreciated by one skilled in the art, the selection of the solvent will depend on the compound (s) sought to be stabilized. Illustrative solvents are conventional laboratory liquid solvents such as water, alkanes, alkenes, alcohols, ketones, aldehydes, ethers, esters, various acids including mineral acids, carboxylic acids, and the like, bases and mixtures thereof. Some specific illustrative solvents are methanol, ethanol, propanol, acetone, acetic acid, hydrochloric acid, tetrahydrofuran, ether and mixed ethers, pentane, hexane, heptane, octane, toluene, xylene and benzene. Water is an especially useful component as a solvent / liquid mixture of the present invention, particularly where the most stable polymorph of a substance is a hydrate. In general, two solvents suitable for conventional liquid recrystallization of the compound of interest are suitable as a solvent in the method herein. The compound (s) of the stable particles of the present invention includes any organic compound capable of existing as a crystalline solid at standard temperature and pressure. A preferred embodiment of the present invention is one in which the particles are composed of one or more organic compounds capable of forming a stable crystalline solid. Preferably, the stable crystalline solid is a network of crystalline structure of discrete organic molecules, ie, non-polymeric. Organic compounds having some pharmacological or therapeutic activity are also preferred. A very preferred are the pharmacological compounds susceptible to the formation of polymorphs. Preferred embodiments further include particles composed of a steroid or sterol, such as estrogen, 17β-estradiol, testosterone, progesterone, cholesterol, or mixtures thereof. These mixtures may also include Oxatomide / Cholesterol, Nifedipine / Cholesterol, Astemizole / Cholesterol, which have non-steroidal components. Stable shaped particles of other organic compounds can also be provided through the present invention, for example, Cisapride, Oxatomide.

Since the method of the present invention results in a significant stabilization of particles of amorphous or metastable crystalline organic compounds, the particles of the present invention can be stored in liquid suspension, such as an aqueous medium, or administered directly to a patient. Since the present invention provides stable forms of existing pharmacological agents, it will be understood by those skilled in the art that the particles of the present invention can be used in accordance with conventional practice in analogous formulations, for example, parenteral administration of microspheres, the administration of pharmacological agents through implants, etc.

DETAILED DESCRIPTION OF THE INVENTION All publications and patent applications mentioned herein are incorporated by reference to the same degree as if each publication or individual patent application was specifically and individually indicated as incorporated by reference. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention pertains. Although any methods and materials similar to those described herein may be used in the practice or testing of the present invention, preferred methods and materials are described. The present invention provides stable shaped particles of one or more molecular, allotropic organic compounds. Alotropic organic compounds are those capable of submerging two or more different physical forms (that is, assuming different crystalline forms or an amorphous form against a crystalline one). Said allotropic species are also referred to as polymorphs or polymorphic species. The shaped, storage stable particles of the present invention optionally further comprise pharmaceutically acceptable excipients, stabilizers and pH regulators, as is commonly known to those skilled in the pharmaceutical art. These stable shaped particles possess an advantageous combination of physicochemical properties. First, the particles are shaped to desired shapes by which they can not result in the more stable crystalline form of the organic compound constituent. The particles are then subjected to a solid state crystallization process which results in the organic compound assuming the more stable crystalline structure, and facilitates the retention of the size and shape of the original particle. The resulting product is a particularly shaped particle composed of one or more molecular organic compounds, each having a uniform crystalline character and possessing a high degree of storage stability. The combination of the uniformity of particle size and shape and the uniformity and stability of the crystal structure of the constituent organic compound leads to the particular predictability to a consistent and biodynamic bioavailability associated. More particularly, the particles are prefabricated to desired specifications, for example, microspheres of particular size and shapes. The particles are then subjected to a solid state crystallization process that stabilizes the compounds of the unrendered particles and the prefabricated size and shape. The resulting particles have a greater uniformity of size and shape, more predictable and uniform profiles of dissolution, and greater storage stability in various forms, for example, in liquid suspension such as aqueous media or other storage liquid, such as lyophilized solid, or just as a powder or a dry solid. By storage, it is meant that the particles have an improved storage life without losing the desired uniform size and shape of the particles., per se. That is, if the particular shape desired is a microsphere, the particles will retain a spherical shape of constant size for periods extending up to several years. As used herein, "storage stable" refers to the retention of the original size and shape of the particle, as well as the pharmacological activity of the active agent over a period of time of at least one month. The present invention also involves a method for crystallizing shaped particles of a compound or mixture of metastable compounds without the dissolution of the particle and consequent loss of the desired shape. The crystallization process is carried out by exposing said particles to a controlled atmosphere saturated with the vapors of a solvent or solvents. The atmosphere is optionally modified in other aspects, for example, pressure, temperature, inert gases, etc. Preferably, the controlled atmosphere is saturated with a solvent vapor but not so much that they effect condensation of said solvent. More particularly, the method of the present invention involves effecting the crystallization of an amorphous or metastable organic compound in a shaped particle without altering the dimensions (eg, size and shape) of the particle, comprising: (i) exposing said particle configured to an atmosphere saturated with the vapor of a liquid, said liquid being a solvent for the organic compound, and (ii) recovering the shaped particle, wherein said organic compound is of a uniform crystalline structure. Alternatively established, the method involves effecting a solid state crystallization of a molecular organic compound in a particle of definite size and shape comprising: (i) exposing said particle to an atmosphere saturated with a solvent for the organic compound; and (ii) recovering said particle, wherein the organic compound in the recovered particle is of a uniform crystalline structure, and said recovered particle has retained the size and shape. The retention of the particle size and shape means that it includes minor variations in the dimensions of the particle, for example, no more than about 15%; and preferably not more than about 10%. The present invention provides a means for making particles of desired dimension without considering the resulting allotropic form of the organic compound. After the particle is fabricated to the desired shape and sizes, solid state crystallization can be effected to crystallize the organic compound to a stable solid state upon storage of a uniform crystal structure. In addition, the solid state crystallization of the present invention can be carried out on particles comprising more than one allotropic organic compound. Preferably, the shaped particle is a microsphere; and, as a result of the present process, the organic compound of the microsphere is ordered in a homogeneous, individual crystalline form without any deterioration in the size and shape of the microsphere. For the purposes of the present invention, the term "Crystallization" refers to a process through which the more stable polymorph of a particular substance is obtained. Recrystallization refers to a process similar to crystallization, except that the organic compound of the particle, instead of being amorphous, was initially only partially crystalline, of a mixed crystalline habit, or crystalline, but of a less stable crystalline form. Unless otherwise indicated, the term crystallization includes recrystallization. The term "solid state crystallization" refers to a crystallization process that is carried out without macroscopic dissolution of the compound being crystallized. As used herein, solid state crystallization includes a crystallization process, wherein an organic compound within a shaped particle is crystallized or recrystallized through exposure to a solvent vapor without loss or alteration of the form or particle size. It will be appreciated by those skilled in the art that, while very fine intermolecular changes will be effected through such crystallization (e.g., creation or rearrangement of the crystal lattice structure of the crystal), the microscopic and / or macroscopic dimensions of the particle they will not be appreciably altered. The term "saturated" when used with reference to the atmosphere, wherein the crystallization is conducted through the atmosphere inside the chamber or enclosure used to maintain the solvent vapors, contains the maximum amount of said solvent in the atmosphere. the vapor phase without effecting visible condensation on the surfaces inside the chamber. The condensation does not include microscopic condensation on the surface of the particles that do not affect its shape. The term "solvent" refers to a liquid at standard temperature and pressure, and one capable of solubilizing an appreciable amount of a specific solid solute. The solid solute will be a particular organic compound. The solids vary from 0-100% in their degree of solubility. See, for example, "Solubility Parameters of Organic Compounds," CRC Handbook of Chemistry and Physics, 62d. Ed., C-699, CRC Press; N. Irving Sax and Richard J. Lewis, Sr., Hawley's Condensed Chemical Dictionary, 11th. Ed. 1079 (1987). For the purposes of the present invention, a liquid will be considered a solvent with respect to a particular solid solute provided that the solute is at least 10% soluble in said liquid.

The term "particle" refers to a discrete collection of a plurality of molecules of one or more organic compounds. As used herein, a particle may be an ordered (e.g., crystalline) collection or a disordered (e.g., amorphous) collection of molecules, or any combination thereof. The term encompasses, among other things, microscopic as well as macroscopic particles, such as powders, microspheres, pellets, implants, and the like. Preferably, the particles are made of microspheres. Preferred microspheres of the present invention range in size from one millimeter to one millimeter, preferably from 1 to 500 microns, and most preferably in the range from 1 to 100 microns, particularly for human use. When the particles are in the pellet form, said particles are usually, but not necessarily, cylindrical with lengths of 1000 to 5000 microns and a diameter of 500 to 1000 microns. These particles can have important applications for veterinary use, and are not injected but rather deposited under the skin. The size and shape of the particle will depend on the intended application and the constituent organic compound. For example, the microsphere size is selected for practical reasons i.e., an appropriate size for administration using a hypodermic needle or to ensure a desired dissolution rate. The term "molecular organic compound" refers to an organic compound that exists as discrete stable (i.e., non-polymeric) molecules and when combined with a plurality of identical molecules is capable of assuming one or more ordered structures. In this way, a molecular organic compound means distinguishing itself from a polymeric species.

The term "metastable" means a state of pseudo-equilibrium of a solid substance, where the content of free energy is greater than that contained in the state of equilibrium. For particular purposes, a substantial or "stable" particle has a crystalline structure whose shape remains unchanged in a standard environment, for example, in air having varying levels of humidity, for an extended period of time. However, it must be understood that "stable" does not indicate infinite stability, but means stable enough, so that the particles remain stable enough for the preservation of their crystalline characteristics during storage and until their application and use and, after they have been administered to a subject, until its total dissolution. The present invention also encompasses stable microspheres contained using a method herein. Said microspheres preferably contain a compound having pharmaceutical applications. The microspheres and pellets of the present invention are useful in therapeutic regimens for humans, as well as for animals. For example, there is currently a need for compositions that achieve sustained release of steroidal growth promoters in food animals to promote the development of such animals. The amount of growth hormone administered to an animal will depend on the particular animal species, the hormone, the duration of treatment, the age of the animal, and the amount of growth promotion desired. Other considerations that are taken into account in the use of hormonal compositions in the treatment of animals are discussed in the patent of US Pat. No. 5,643,595, which is incorporated herein by reference. The particles of the present invention can be particularly configured for optimum delivery through injection by varying the particle size. As discussed above, the microspheres of the present invention are stable in aqueous fluids, and thus may be operable for parenteral injection. The modes of administration include, but are not limited to, intravenous (IV), intra-arterial (IA), intra-muscular (IM), intra-dermal, subcutaneous, intra-articular, cerebrospinal, epidural, intraperitoneal, etc. In addition, the compounds of the present invention can be administered through an oral route, either as an aqueous suspension or as a lyophilized product. Other routes of administration are also acceptable, including topical application, in the eye, or through inhalation in the form of drops or vapor. The dosage form according to the present invention can take the form of a microsphere powder in vials / ampoules, ready to be prepared as suspensions, or it can take the form of suspensions already prepared, packed in injectable ampoules or directly in syringes, ready to be administered in medicine for human beings or veterinarians. The suspension medium can be water, a saline solution, an oil, containing pH regulators, surfactants, preservatives, commonly used by pharmacotechnicians to prepare injectable substances or any other substance or combination that does not endanger the physical and chemical integrity of the substances in suspension and that is suitable for the organism that receives it. If it is desired to avoid a sudden initial increase in the level of active ingredient in the internal environment of the recipient organism, it will be preferable in the case of ready-to-use suspensions to use liquid vectors wherein said active ingredients are practically insoluble. In the case of active substances partially soluble in the warm liquid vector, but insoluble at cold temperature, it is preferred, from the pharmacological point of view, to avoid the formation of precipitates (effect of "cake formation") by preparing formulations in the form of Separate microsphere powder and liquid vector that will be mixed only at the time of injection. In veterinary applications, where the duration of the desired effect can be very long (for example, the period of lactation of the adult female), diameters of a few hundred miera can be used. If it is desired to limit the diameter of injection syringe needles for patient comfort, the diameter of the microspheres should be limited to 300 microns, and most preferably 100 microns. In contrast, during very short periods of effect (for example, circadians), the diameter of a microsphere can be reduced to 5 microns.

For most applications in medicine for humans (duration of action of the active ingredient between a circadian cycle and a menstrual cycle), it is preferred to use microspheres whose diameter is between 5 and 100 microns, depending on the combinations of active substances / carrier substances. A separation of microspheres according to their diameter can be carried out during the manufacturing process using known processes: for example, through cyclonic separators, through screening using air suction or sieving in an aqueous medium. In practice, it is sufficient if more than 70% of the microspheres have diameters between 70% and 130% of a specific diameter. If necessary, the solution and ideal curve, determined by the proposed application, can be approximated by mixing lots with different suitable diameters. In addition, particles that do not meet specifications can be recirculated. The mechanism through which substances in a solid state crystallize in the presence of vapors containing at least one solvent has not yet been established. The crystallization process can be well conformed, with respect to the effect of the solvents, to the traditional principles that are applied in saturated solutions and in molecular mobility. It is possible that some rotational movement or molecular transfer occurs, which seems to depend on the particular type of solvent used and the vaporization temperature. Hancock et al. Et al., "Characteristics and Significance of the Amorphous State in Pharmaceutical Systems" J. Pharm. Sci., Vol. 86, No. 1, 1-12 (1997). However, it is evident that the temperatures at which the crystallization is obtained are below the glass transition temperatures and, in fact, only agree with those required for the vapor pressure of the solvent. Without wishing it to be bound by theory, it is contemplated that the vapor molecules of the solvent or solvents may form microcondensations and minute accumulations of solvent on the surface of particles that will be crystallized, thus bringing enough energy to the surface molecules of the solid particles to form organized structures (for example, crystalline domains). By the same means, if present in the vapor, water molecules are made available for the formation of hydrates, when required for stable polymorphs. Once the process of organization and / or water absorption begins at the surface, it is possible that the crystallization process gradually extends into the particle without the need to make contact with or dissolve within the solvent. If this is correct, there are two factors that seem to indicate that these microcondensions or molecular agglomerations are extremely tiny. First, if enough solvent condensation occurs on the surface of the particle, the solvent could at least partially dissolve it and modify its shape. To avoid any partial dissolution, the amounts deposited by the steam must be extremely minute. Secondly, during exposure to solvent vapors, the particles, due to their small size and large quantity, inevitably come into contact with each other. If any dissolution of the particles on the surface occurs, as could happen if the substantial amounts of vapors deposited were not very minute, the particles could stick together and form clumps or agglomerates. Under the conditions described here, this does not happen.

EXAMPLES The following examples will illustrate how a substance or mixtures of substances are transformed from metastable to more stable crystalline structures according to the method of the present invention.

EXAMPLE 1 Microspheres of 17β-estradiol This and other substances were melted / sprayed into droplets and then frozen in microspheres that were suspended in a medium of water for extended release injectable products. The 17ß-estradiol microspheres obtained after freezing their drops sprayed at -50 ° C, showed a high proportion of amorphous matter. Heating these microspheres sufficiently allowed the amorphous matter to crystallize to an anhydrous polymorph. However, despite being fully crystallized, these microspheres remained stable at room temperature, but unstable when placed in water, due to the fact that the stable polymorph is a hemihydrate (Salóle, The Physicochemical Properties of Estradiol, J. Pharm- Biomed-Anal., 1987: 5 (7), 635-648; Jeslev et al., Organic Phase Analysis, II. Two unexpected cases of pseudopolymorphism, Arch. Pharm. Chemi. Sci. Ed., 1981, 9, 123-130). Thus, in aqueous solution, the substance spontaneously reversed to this more stable polymorph and in doing so restructured its crystalline arrangement in forms that differ from the microsphere. When these microspheres were placed in a container of approximately 7 liters and exposed for 24 hours at 20-25 ° C to the vapors of 13.5 ml of a mixture (50/50) of ethanol and water, maintained in a porous cellulose material , the initially amorphous microspheres were directly crystallized in the presence of vapors to the stable hemihydrate polymorph and then were stable when placed in water. To evaluate the stability of the crystallized microspheres of 17β-estradiol, the microspheres were placed in aqueous solution at 40 ° C and observed through an optical microscope after 274 days. In this way, the stability in the water of the microspheres containing the hemihydrate form can be verified using optical microscopy. The residual ethanol present in the microspheres was less than 0.01%.

EXAMPLE 2 Testosterone microspheres Several authors have reported that testosterone has several polymorphs, of which two forms of hydrates are stable in water (Frokjaer et al., Application of Differential Scanning Calorimetry to the Determination of the Solubility of a Metastable Drug, Arch. Pharm. Chemi. Ed., 2, 1974, 50.59; Frokjaer et al., Dissolution Behavior Involving Simultaneous Phase Changes of Metastable Drugs, Arch. Pharm. Chemi, Sci. Ed., 2, 1974, 79-54; Thakkar et al., Micellar Solubilizarion of Testosterone III Dissolution Behavior of Testosterone an Aqueous Solutions of Selected Surfactants, J. Pharm. Sci., Vol. 58, No. 1, 68-71). The testosterone microspheres, immediately after being produced through the same spraying / freezing as for 17β-estradiol, showed an equally high amorphous content. Heating of the microspheres at 117 ° C for 23 hours crystallized them to an anhydrous polymorph similar to that found in the commercial starting material. However, when these microspheres were placed in water, the anhydrous polymorph spontaneously became a hydrated structure, a conversion that caused the microspheres to lose their shape. In contrast, when these microspheres were placed in a container of approximately 7 liters and exposed for 24 hours at 20-25 ° C to the vapors of 40 ml of a mixture (80-20) of acetone and water maintained in a Porous cellulose, initially the amorphous microspheres were directly crystallized in the presence of the vapors in the stable hydrate polymorphs mentioned above. These crystalline particles exhibited storage stability when placed in water. To evaluate the stability of the testosterone microspheres, the microspheres were placed in an aqueous solution at 40 ° C and visualized 54 days later by optical microscopy. For comparison, non-crystallized testosterone microspheres (only frozen by fusion) were also placed in an aqueous solution and visualized after 40 days. The stability in the water of the microspheres containing the hydrate polymorphs against the non-crystallized microspheres was evident by comparing the photographs of the optical microscopy. The residual ethanol present in the microspheres was less than 0.01%.

EXAMPLE 3 Progesterone microspheres The progesterone microspheres, immediately after being produced through the same spraying / freezing as for the previous substances, showed some crystallization in the polymorphs I and II. No polymorph of hydrate has been reported for progesterone. However, when the microspheres were applied in a container of approximately 7 liters and exposed for 4 hours at 20-25 ° C to the vapors of 13.5 ml of a mixture (50-50) of ethanol and water maintained in a cellulose material The porous, initially amorphous microspheres were directly crystallized in the presence of vapors to stable polymorph I and were then stable when placed in water. To evaluate the stability of the crystallized progesterone microspheres, the microspheres were placed in an aqueous solution at 40 ° C and observed through optical microscopy after 187 days. It should be noted that in the case of progesterone, the use of solvent vapors also caused the conversion of polymorph II, present in the mixture of structures found after the spray-freeze, to polymorph I, as observed through DSC. In addition, in the case of progesterone, exposure to solvent vapors was also successfully obtained with a mobile system. The microspheres were placed in a sealed 1.6-liter crystallization chamber rotating at 5 RPM and placed in contact with ethanol vapors for 24 hours. In both experiments, the residual ethanol present in the microspheres was less than 0.01%.

EXAMPLE 4 Microspheres of Astemizole To demonstrate that the method of the present invention was successful in forming stable crystals of organic compounds other than steroids and sterols, astemizole microspheres were subjected to solvent vapor treatment. Immediately to be produced through the same spraying / freezing for the previous substances, the microspheres of astemizole also showed a high amorphous content. However, when 100 mg of the microspheres were placed in a container of approximately 0.5 liters and exposed for 24 hours at 30CC to 0.5 ml vapors of ethyl acetate kept in a porous cellulose material, the initially amorphous microspheres were directly crystallized in the presence of vapors to a stable polymorph. Similar results were obtained in another experiment using acetone. To evaluate the stability of the microspheres of astemizole, the microspheres were placed in aqueous solution at 40 ° C and observed through optical microscopy after 76 days.

EXAMPLE 5 Astemizole Pellets In the case of astemizole pellets, immediately after freezing the molten starting material at -50 ° C, the pellets showed a high content of amorphous material. However, the exposure of 150 mg of astemizole pellets in a container of approximately 0.5 liters for 24 hours at 30 ° C to the vapors of ethyl acetate contained in a porous cellulose material led to the crystallization of the pellets without any modification in the form of the particle. Similar results were obtained using acetone in another experiment.

EXAMPLE 6 Cholesterol microspheres Immediately after being produced through the same spraying / freezing as for the previous substances, the cholesterol microspheres showed an amorphous content. No polymorph has been reported for cholesterol. When 100 mg of the microspheres were placed in a container of approximately 0.5 liters and exposed for 8 hours at 30 ° C to the vapors of 1 ml of acetic acid maintained in a porous cellulose material, the initially amorphous microspheres were completely crystallized.

Crystallization of Mixtures of Substances The mixing of different substances into particles of frozen-fused shaped ingredients can provide important advantages. Among them are: modulation of dissolution rates, reduction of the melting point, dilution of the active ingredients, improvement of the chemical stability of the important ingredients, etc. In this way, the ability to crystallize particles composed of mixtures of substances greatly increases the scale of applications of frozen solids by fusion in health areas and other areas. Many mixtures of substances can be melted and frozen. However, due to the different physical characteristics of each component, these mixtures tend to form complex metastable structures after freezing and, with the exception of eutectic mixtures, it is impossible to crystallize them since one of the substances can melt before reaching the transition point temperature. As explained above, the particles comprising pluralities of allotropic organic compounds are likewise suitable for the solid state crystallization of the present invention. The crystallization is complete and the resulting particles are stable in both water and dry environments at the usual storage and use temperatures.

EXAMPLE 7 Microspheres of a Mix of 40% 17β-Estradiol and 60% Cholesterol The microspheres of this mixture were obtained by melting together the components and, as for the pure substances, sprayed in droplets and frozen to microspheres. Initially they showed a high amorphous content. When the microspheres were placed in a container of approximately 7 liters and exposed for 24 hours at 30 ° C to vapors of 8 ml of ethanol maintained in a porous cellulose material, the initially amorphous microspheres were completely crystallized in the presence of the vapors. The microspheres were dried at 60 ° C under vacuum for 24 hours, and the residual ethanol present in the microspheres was less than 0.01%. To evaluate the stability of the microspheres, the non-crystallized microspheres (only melt frozen) and the microspheres according to the present invention were placed separately in an aqueous solution at 40 ° C and observed through optical microscopy after 82 hours. days. As observed through the optical microscope, the crystallized microspheres according to the present invention remained stable for a time when they were placed in water, whereas the non-crystallized microspheres did not.

In vivo Stability In the case of medicinal drugs injected or implanted with slow release, the physical integrity of the particles after their administration to the patient is essential to ensure the desired delivery rates and the ability to reproduce the effect. In this way, the in vivo stability of the microspheres described in the previous Example was verified in male New Zealand rabbits. The photographs of the optical microscope taken 1, 4, 7 and 14 days after the intramuscular injection showed that the microspheres remained whole, until finally they were dissolved. For comparison, microspheres that had not been crystallized were also injected. His photographs of the optical microscope showed that these microspheres changed to non-spherical forms.

EXAMPLE 8 Microspheres of a Mixture of 10% 17β-Estradiol and 90% Cholesterol For the previous example, the microspheres of this mixture were obtained by melting the components together, sprayed in droplets and frozen to microspheres. Initially, they showed a high amorphous content. When the microspheres were placed in a container of approximately 7.0 liters and exposed for 24 hours at 5 ° C to the vapors of 8 ml of ethanol maintained in a porous cellulose material, the initially amorphous microspheres were completely crystallized in the presence of the vapors The microspheres were then dried at 60 ° C under vacuum for 24 hours, and the residual ethanol present in the microspheres was less than 0.01%. To evaluate the stability of the crystallized microspheres, they were placed in aqueous solution at 40 ° C and observed through an optical microscope after 141 days.

EXAMPLE 9 Microspheres of a Mix of 95.2% Progesterone and 4.8% of 17ß-st radius! As for the previous examples, the microspheres of this mixture were obtained by melting the components together, sprayed in droplets and frozen in microspheres. Initially, they showed a high amorphous content. When the microspheres were placed in a container of approximately 7 liters and exposed for 24 hours at 20-25 ° C to the vapors of 2 ml of ethanol maintained in a porous cellulose material, the initially amorphous microspheres were completely crystallized in the presence of the vapors. The microspheres were then dried at 60CC under vacuum for 24 hours, and the residual ethanol present in the microspheres was less than 0.01%.

EXAMPLE 10 Microspheres of a Mix of 60% Progesterone and 40% Cholesterol As for the previous examples, the microspheres of this mixture were obtained by melting the components together, sprayed in droplets and frozen in microspheres. Initially they showed a high amorphous content. When the microspheres were placed in a container of approximately 7 liters and exposed for 24 hours at 30 ° C to the vapors of 2 ml of ethanol maintained in a porous cellulose material, the initially amorphous microspheres were completely crystallized in the presence of the vapors The microspheres were then dried at 60 ° C under vacuum for 24 hours, and the residual ethanol present in the microspheres was less than 0.01%. Thus, it is evident that the method of the present invention is widely applicable to form crystallized, stable particles, microspheres and pellets of a variety of organic compounds and mixtures that maintain their shape in aqueous solution. Therefore, the method of the present invention should find important utility in the manufacture of pharmaceutical compositions and pharmaceutical products, particularly where the treatment requests administration of the pharmaceutical product in a slow release formulation. Although some embodiments of the present invention have been shown or described herein, it will be apparent to those skilled in the art that various modifications to the crystallization process can be made without departing from the spirit and scope of the present invention.

Claims (25)

1. - A method for effecting a solid state crystallization of an allotropic organic molecular compound in a particle of definite size and shape, comprising: (i) exposing said particle in an atmosphere saturated with a solvent for the organic compound; and (ii) recovering said particle, wherein the organic compound in the recovered particle is of a uniform crystalline structure, and said recovered particle has retained its size and shape.

2. The method according to claim 1, wherein the particle is selected from the group consisting of a lyophilized solid, a pellet and an implant.

3. The method according to claim 1, wherein the particle is a microsphere.

4. The method according to claim 1, wherein the particle is a microsphere with a diameter between about 1 and about 1000 microns.

5. The method according to claim 1, wherein the particle is a microsphere with a diameter between about 10 and about 300 microns.

6. The method according to claim 1, wherein the first particle has been formed through freezing by melting said organic compound to a microsphere.

7. The method according to claim 1, wherein said solvent is selected from the group consisting of: water, ethanol, acetone, acetic acid, toluene, benzene.

8. The method according to claim 1, wherein said organic compound is a pharmacotherapeutic agent that exhibits polymorphism.

9. The method according to claim 1, wherein the organic compound is a sterol or steroid.

10. The method according to claim 9, wherein said sterol or steroid is selected from the group consisting of 17β-estradiol, estrogen, testosterone, progesterone, cholesterol, and mixtures thereof.

11. The method according to claim 1, wherein said atmosphere is maintained at a temperature sufficient to effect vaporization of the solvent, but below the melting point of said organic compound.

12. The method according to claim 1, wherein the recovered particle is subsequently stored in dry form or in an aqueous medium.

13. A stable particle to the storage of a definite size and shape, and comprising an allotropic organic compound of uniform crystalline structure, said organic compound retaining the crystal structure, and said particle retaining the size, and the storage form in a aqueous medium for at least one month.

14. The particle according to claim 13, comprising a plurality of allotropic organic compounds.

15. The particle according to claim 13, further comprising an additive selected from the group consisting of pharmaceutical excipients, pH regulators, stabilizers, and combinations thereof.

16. The particle according to claim 13, wherein the particle is a microsphere.

17. The particle according to claim 13, wherein the particle is a microsphere with a diameter between about 1 and about 1000 microns.

18. The particle according to claim 13, wherein the particle is a microsphere with a diameter between about 10 and 300 microns.

19. The particle according to claim 13, wherein the desired crystalline form of the allotropic organic compound is a hydrate.

20. The particle according to claim 13, wherein the allotropic organic compound is a steroid or sterol.

21. The particle according to claim 20, wherein the steroid or sterol is selected from the group consisting of 17β-estradiol, estrogen, testosterone, progesterone, cholesterol and mixtures thereof.

22. The particle according to claim 13, wherein said allotropic compound is astemizole, Cisapride or Oxatomide.

23. - A method for effecting a solid state crystallization of a mixture containing at least one allotropic organic molecular compound, wherein said mixture has been frozen to a particle of definite size and shape, comprising: (i) exposing said particle to an atmosphere saturated with a solvent for the organic compound; and (ii) recovering the particle, wherein the organic compound in the recovered particle is of a uniform crystalline structure, and the recovered particle has retained said size and shape.

24. The method according to claim 23, wherein said mixture, which contains at least one allotropic organic compound, contains a steroidal component.

25. The method according to claim 24, wherein said mixture is selected from the group consisting of Oxatomide / Cholesterol, Nifedipine / Cholesterol, and Astemizole / Cholesterol.