HK1036017B - Stable shaped particles of crystalline organic compounds - Google Patents

Description

Stable shaped particles of crystalline organic compounds

Background

Many substances are known to have a tendency to crystallize, and they crystallize in different ways depending on their crystallization conditions. The different crystalline structures resulting from the crystallization of a particular substance are referred to as polymorphs or pseudopolymorphs. It is also known that when they melt and rapidly cool below their melting point, i.e. melt-congeal, the atoms or molecules that form the majority of the substance take some time to arrange themselves in the most natural order of the atmosphere in which they are located. Thus, they remain in an unstable amorphous or semi-amorphous state or constitute metastable polymorphs.

Metastable polymorphs may be tautomeric, a property of certain substances, meaning that the substance may exist in more than one crystal form (Giron, thermal analysis and calorimetry in polymorph and solvate characterization, Thermochimica Acta, 248(1995) 1-59; Parker, dictionary of scientific and technical terms, McGraw Hill, Inc., 1984, 541; Hancock et al, characterization and importance of amorphous states in pharmaceutical systems, J.Pharm.Sci., Vol86, No.1, 1997, 1-12). In general, there is a relationship between the various crystal forms or nodules of a tautomeric substance, one crystal form being stable above a transition point temperature and the other crystal form being stable below the transition point temperature. Therefore, the habit of the crystal is constantly changing and reversible depending on the ambient conditions.

The metastable polymorph typically transforms into a more stable structure over a period of time. This natural crystallization process is called "aging" and occurs naturally over a period of time without human intervention. This natural "aging" process is often lengthy and unpredictable, and therefore costly and potentially dangerous, particularly in pharmaceutical production. Since the aging process is mainly dependent on atmospheric factors, unpredictability results. Yu, "the relationship of thermodynamic stability of polymorphs deduced from melting data", J.Pharm.Sci., Vol 84, No.8, 966-.

However, stable crystalline materials are often required to have optimal and reliable biological activity and bioavailability. If metastable particles, such as microspheres or pellets, are placed in an aqueous medium before full crystallization occurs, deformation of the particles or even total destruction of the particles may occur in about a few hours or so.

Moreover, different polymorphs of a particular substance will have different dissolution rates, which leads to lack of stability and loss of homogeneity between different batches of the same drug. For example, Haleblian et al report a difference in dissolution rates between prednisolone polymorphs. Haleblian et al, "isolation and characterization of certain solid-phase prednisolone flurandrenes", J.Pharm.Sci., Vol.60, No.10, 1485-1488 (1971).

For pharmaceutical use, obtaining stable crystals is particularly important, since administration of therapeutic compounds usually requires suspensions in aqueous solutions suitable for injection. Even if the compound is not first suspended in an aqueous medium, it will contact a water-based biological fluid when administered to a patient. This also applies to pellets and implants that are surgically or otherwise placed into the body. To ensure physical integrity of the shaped particles and uniform release of the active agent, it is necessary to ensure complete crystallization prior to administration.

Some workers have attempted to improve the stability of therapeutic compounds by inducing crystallization. For example, Matsuda et al propose a dispersion drying method using temperature control to modify the crystal structure. Matsuda et al, "physicochemical Properties of spray-dried phenylbutazone polymorphs", J.pharm.Sci., Vol 73, No.2, 73-179 (1984).

However, since dissolution of solids also involves surface erosion, in addition to solubility, the shape and size of the therapeutic particles must also be considered. Carstensen, "pharmaceutical principles of solid and solid dosage forms," Wiley Interscience, 63-65, (1977). Thus, when a pharmaceutical compound is administered as a solid or suspension, maintaining a particular shape and size becomes an important factor in ensuring control and reproducibility of bioavailability and biokinetics.

In view of these, Kawashima et al proposed a method for producing spherical crystals of tranilast by using two mutually incompatible solvents and converting the resulting polymorph by heating. Rawashima et al, "characteristics of tranilast anhydrate and tranilast monohydrate polymorphs when crystallized by a two-solvent modification of the spherical crystallization technique," J.pharm.Sci., Vol 80, No.5, 472-477 (1981).

It has also been reported that the natural aging process can be accelerated by heating. Ibrahim et al, "phenylbutazone polymorph: nature and compression behavior of the crystals ", j.pharm.sci., Vol 66, No.5, 669-; hancock et al, the characterization and importance of the amorphous state in pharmaceutical systems, J.pharm.Sci., Vol86, No.1, 1-12 (1997). However, in some cases heating is required, which compromises the integrity or shape of the substance. In several cases where heating is used, it is difficult or even impossible to obtain reproducible results, stability and control of the crystal size in the particle range.

In addition, in some cases, the most stable polymorph of a particular substance is a hydrate, which means that it is not possible to obtain the desired polymorph by heating, because such a result leads to dehydration. Furthermore, heating is rarely suitable for stable crystallization in the case of mixtures. Therefore, as a method for obtaining a stable polymorph, the heating method, although superior to the aging method, is significantly limited.

Other workers have investigated the use of solvent vapor to induce crystallization of polymeric materials. This achievement includes the well-established crystallization and modification of the mechanical properties of the polymer as described in us patent 4,897,307. See also Muller, A.J. et al, "melting behavior, mechanical Properties and fracture of crystalline polycarbonates", Latinoamericina de Metalluria materials, 5(2), 130-141 (1985); and Tang, F. et al, "Effect of solvent vapor on the optical Properties of Pr/sub 4VOPe in polymethyl methacrylate," Journal of applied Physics, 78(10), 5884-7 (1995).

Tang et al used organic solvent vapors to convert the polymer matrix Pr4VOPc dye (vanadyl phthalocyanine with 4 propyl substituents) from the glassy phase I to the crystalline phase II. Muller and Paredes describe crystallizing polycarbonate polymers by incorporating a solvent or plasticizer into the amorphous state. To the best of the inventors' knowledge, this method has not been used to form stable melt-congealed organic compounds and crystals of mixtures.

Summary of The Invention

The present invention provides reproducible, stable crystalline organic compound particles. The stable crystalline organic compound particles of the present invention may be uniform particles of a single organic compound, or they may be a mixture of two or more organic compounds. The stabilized particles of the invention maintain a constant shape and size during long term storage, such as in an aqueous suspension. The stable particles can be made to a uniform size and shape and they will retain said size and shape despite prolonged storage; and is therefore particularly advantageous in pharmaceutical formulations. The invention further provides a method for obtaining the renewable, stable particles. The process involves exposing the above-described shaped particles, in which one or more organic compounds are present in crystalline, amorphous or some metastable form, to an atmosphere saturated with solvent vapour. The solvent is composed of one or more liquids in which at least one or more organic compounds are soluble.

The method of the present invention may provide several advantages. Since this method does not drive out water molecules and therefore water molecules can be incorporated into the crystalline network during formation, it is applicable to materials in which the most stable polymorph is a hydrate. Since the process avoids the use of high temperatures, it is suitable for use with substances that are not heat-resistant. And this method allows the formation of stable structures involving mixtures of substances, which cannot be obtained by heating, in addition to the eutectic mixture-composition.

More particularly, the present invention relates to a method of crystallizing or recrystallizing an amorphous or metastable crystalline organic compound or mixture. The method comprises the steps of (i) exposing said compound or mixture to an atmosphere saturated with one or more liquid vapors, at least one of which must be a solvent for said compound or mixture, for a time sufficient to convert said metastable compound or mixture to a stable crystalline compound or mixture; and (ii) recovering the stable, crystalline compound or mixture for storage or use.

The method can be performed using any chamber in which volume, temperature, air content and pressure can be controlled. The chamber can contain air saturated with the desired solvent vapor. The saturation point is reached when the vapor fills the chamber and does not cause condensation on the chamber or particle surface.

Preferably, the particles are formed into shaped particles, such as microspheres, pellets or implants. Particles having uniform and reproducible surface areas are particularly preferred. This may be affected by melt-congealing. Further, preferably, the shaped particles are made into particles having a uniform particle size or range of particle sizes. For this purpose, the methods described in U.S. Pat. Nos. 5,633,014, 5,643,604 and 5,360,616, which are incorporated herein by reference, may be used. Alternatively, any suitable method that produces metastable crystalline agglomerates may be used. If the process involves crystallisation of a mixture, the mixture may be a eutectic or an off-eutectic mixture.

The particles are placed in a chamber or other suitable enclosed space using any suitable method such that they are exposed to the solvent vapor, but are not immersed in or otherwise contacted with the liquid solvent. The particles are stationary or moving within the chamber.

The time period necessary to achieve crystallization according to the process of the invention will vary depending on various physicochemical characteristics consistent with the established elements. For example, the optimal time of exposure will vary depending on the shape and size of the particles, the chemical composition of the particles, the solid state form of the particles (i.e., amorphous form, metastable crystalline form), the type and concentration of solvent used, and the temperature of the treatment. Usually several seconds to 48 hours, or more preferably 1 to 36 hours, are suitable. The above-mentioned partial crystallization of the particles does not appear to change these time ranges. The optimum exposure time will vary depending on the solvent system used, the organic compound to be crystallized, and other variables, and is within the skill of one of ordinary skill in the art. As described below, an exposure time of 24 hours is generally effective.

One advantage of the present invention is that it is suitable for use with thermolabile substances, since the process of the present invention avoids the use of high temperatures. Thus, the applicable temperature range is broad and depends on the particular compound. Typically, the temperature of the vapor is sufficient to vaporize the solvent, but below the melting point of the particles.

The solvent used in the process of the invention may be any reagent which acts as a solvent for the organic compound of interest. The choice of solvent will depend on the compound to be stabilized, as known to those of ordinary skill in the art. Examples of such solvents are conventional laboratory liquid solvents such as water, alkanes, alkenes, alcohols, ketones, aldehydes, ethers, esters, various acids including inorganic acids, carboxylic acids, and the like, bases, and mixtures thereof. Examples of some specific solvents are methanol, ethanol, propanol, acetone, acetic acid, hydrochloric acid, tetrahydrofuran, ethers and mixed ethers, pentane, hexane, heptane, octane, toluene, xylene and benzene. Water is a particularly useful component of the solvent/liquid mixture of the present invention, particularly when the most stable polymorph of the material is a hydrate. In general, solvents suitable for conventional liquid recrystallization of the compound of interest are suitable as solvents for the present method.

The constituent compounds of the stable particles of the present invention include any organic compound that can exist in a crystalline solid form at standard temperature and pressure. A preferred embodiment of the present invention is a particle comprised of one or more organic compounds capable of forming a stable crystalline solid. Preferably, the stable crystalline solid is a lattice of discrete organic molecules, i.e. not a polymer.

Organic compounds having certain pharmacological or therapeutic activities are also preferred. Further preferred are said pharmacological compounds which readily form polymorphs. Preferred embodiments also include particles comprised of a steroid or a sterol, wherein the steroid or sterol comprises estrogen, 17 β -estradiol, testosterone (testosterone), progesterone, cholesterol, or mixtures thereof. These mixtures may also include olmesartan/cholesterol, niphedrine/cholesterol, astemizole/cholesterol, which contain a non-steroidal component. The invention also provides stable shaped particles of other organic compounds, such as cisapride and oxamil.

Because of the significant stability of the amorphous or metastable crystalline organic compound particles produced by the method of the invention, the particles of the invention may be stored in liquid suspensions, such as aqueous media, or administered directly to patients. Since the present invention provides stable forms of existing pharmacological agents, one skilled in the art will appreciate that the particles of the present invention may be used in accordance with conventional practices for analogous formulations, such as parenterally administered microspheres, administration of pharmacological agents via implants, and the like.

Detailed Description

All publications and patent applications cited herein are incorporated herein by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described.

The present invention provides shaped particles stabilized with one or more allotropic molecular organic compounds. Allotropic organic compounds are those that are capable of assuming two or more different physical forms (e.g., assuming different crystalline forms or an amorphous form as opposed to a crystalline form). The allotropic species is also referred to as a polymorph or polymorphic species.

The storage stable shaped particles of the present invention may be free of or further comprise pharmaceutically acceptable excipients, stabilizers and buffers commonly known in the pharmaceutical art.

These stable shaped particles have a beneficial combination of physicochemical properties. First, the particles are formed into the desired shape by a process that may not result in the most stable crystalline form of the constituent organic compounds. The particles then undergo a solid state crystallization process, wherein the process produces an organic compound that exhibits the most stable crystalline structure and facilitates the maintenance of the original particle size and shape. In particular, the resulting product is made into particles composed of one or more molecular organic compounds each having uniform crystalline characteristics and having high storage stability.

Combining the uniformity of particle size and shape and the uniformity and stability of the constituent organic compound crystalline structure can provide unique predictability and consistent bioavailability and associated biokinetics.

More specifically, the particles are preformed into desired specifications, such as microspheres of a particular size and shape. The granules are then subjected to a solid state crystallization process that stabilizes the granular compound and does not lose the pre-made size and shape. The resulting particles have greater uniformity of particle size and shape, more uniform and predictable dissolution profiles, and greater storage stability, wherein the particles can be stored in various forms, such as in liquid suspensions such as aqueous media or other storage liquids, in freeze-dried solid form, or in powder or dried solid form alone. By storage stable is meant that the particles have an improved shelf life without losing the desired uniform particle size and shape of the particles themselves. That is, if the desired particle shape is a microsphere, the particles will remain spherical of constant size for a period of time in excess of several years.

Storage stable as used herein means that the particles retain their original size and shape and the pharmacological activity of the active agent over a period of at least one month.

The invention also relates to a method for crystallizing shaped particles of a metastable compound or mixture of compounds without dissolving the particles and without losing the desired particle shape. The crystallization process is achieved by exposing the particles to a controlled atmosphere saturated with solvent vapor. The atmosphere may be unchanged or otherwise changed, such as changing pressure, temperature, inert gas, and the like. Preferably, the controlled atmosphere is saturated with solvent vapor but not so much so that the solvent condenses.

More particularly, the present method relates to a method of crystallizing an amorphous or metastable organic compound in a shaped particle without altering the diameter (e.g., size and shape) of the particle, comprising: (i) exposing the shaped particles to an atmosphere saturated with a vapor of a liquid, the liquid being a solvent for the organic compound; and (ii) recovering the shaped particles, wherein the organic compound has a uniform crystalline structure.

Stated another way, the present method relates to a method of solid state crystallization of a molecular organic compound in particles of defined size and shape, comprising: (i) exposing the particles to an atmosphere saturated with solvent vapor of the organic compound, and (ii) recovering the particles, wherein the organic compound in the recovered particles has a uniform crystalline structure, and the recovered particles retain the size and shape. Maintaining the size and shape of the particles means that the change in particle size is small, e.g., no more than about 15%; and preferably no more than about 10%.

The present invention provides a method of making particles of a desired size without involving the resulting allotrope of an organic compound. After the particles are formed into the desired shape and size, solid state crystallization can be carried out to crystallize the organic compound into a storage stable solid state having a uniform crystal structure. Furthermore, the solid state crystallization of the present invention can be carried out on particles composed of more than one allotropic organic compound.

Preferably, the shaped particles are microspheres; and as a result of the process, the organic compounds of the microspheres are arranged in a single, uniform crystalline form without any disruption to the size or shape of the microspheres.

For the purposes of the present invention, the term "crystallization" refers to the process by which the most stable polymorph of a particular substance is obtained. Recrystallization refers to a process similar to crystallization, except that the organic compound in the particles, rather than the amorphous material, is initially only partially crystalline, consisting of mixed nodules, or crystalline, consisting of poorly stable crystalline forms. 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. Solid state crystallization, as used herein, includes a crystallization process wherein the organic compound in the shaped particles is crystallized or recrystallized without loss or alteration of the shape or size of the particles by exposure to solvent vapor. Those skilled in the art will appreciate that while this crystallization will cause subtle intermolecular changes (e.g., creation or rearrangement of a lattice structure), the microscopic and/or macroscopic particle sizes will not change significantly.

The term "saturated" when used in reference to a crystallization atmosphere means that the atmosphere within the chamber or enclosure used to retain the solvent vapor contains the maximum amount of the solvent in the vapor phase without causing condensation on visible interior surfaces of the chamber. Agglomeration does not include agglomeration on microscopic particle surfaces that do not affect particle shape.

The term "solvent" refers to a liquid that is at standard temperature and pressure and is capable of dissolving an appropriate amount of a specified solid solute. The solid solute is a specific organic compound. The solubility of solids varies from 0 to 100%, see for example "solubility parameters for organic compounds", CRCHandwood 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 is considered to be a solvent for a particular solid solute, provided that at least 10% of the solute is dissolved in the liquid.

The term "particle" refers to a discrete aggregation of a plurality of molecules of one or more organic compounds. As used herein, particles may be molecularly ordered aggregates (e.g., crystalline) or disordered aggregates (e.g., amorphous), or any combination thereof. The term encompasses micro as well as macro particles such as powders, microspheres, pellets, implants, etc., among others.

Preferably, the particles are composed of microspheres. Preferred microspheres of the present invention are in the range of from 1 micron to 1 millimeter in size, more preferably from 1 to 500 microns, and most preferably from 1 to 100 microns, particularly for human applications. When the particles are in pellet form, the particles are typically, but not necessarily, cylinders of 1000-. These particles may have important applications in the veterinary field and are not injected but deposited under the skin.

The size and shape of the particles depends on its use and the constituent organic compounds. For example, the size of the microspheres may be selected for practical reasons, i.e. a particle size suitable for administration through a hypodermic needle or for maintaining a desired dissolution rate.

The term "molecular organic compound" refers to an organic compound that exists as stable discrete molecules (i.e., non-polymeric) and is capable of assuming one or more ordered crystalline structures when combined with a plurality of identical molecules. Thus, molecular organic compounds are distinct from polymeric species.

The term "metastable state" refers to a pseudo-equilibrium state of a solid substance in which the free energy content is higher than that contained in the equilibrium state. For our specific purpose, a "stable" substance or particle has a crystalline structure whose shape remains unchanged for a long period of time under standard atmospheric conditions, for example in air with a varying moisture content. It should be understood, however, that "stable" does not mean infinite stability, but rather sufficient to allow the particles to retain their crystalline characteristics during storage until the time of their use and after administration to a subject until their complete dissolution.

The invention also encompasses stabilized microspheres obtained by the present method. Preferably, the microspheres comprise a pharmaceutically acceptable compound. The microspheres and pellets of the invention are useful in human and animal treatment regimens.

For example, there is a need for a composition that will provide sustained release of a steroid growth promoting agent in food to an animal in order to promote growth of the animal. The amount of growth hormone administered to an animal will depend on the species of the particular animal, the hormone, the treatment period, the age of the animal and the amount of growth promoting desired. Other factors to be considered in the treatment of animals with hormone compositions are discussed in U.S. patent 5,643,595, which is incorporated herein by reference. In particular, by varying the size of the particles, the particles of the present invention can be made into the optimum form for administration by injection.

As noted above, the microspheres of the present invention are stable in aqueous liquids and thus can be used for parenteral administration. Modes of administration include, but are not limited to, Intravenous (IV), Intraarterial (IA), Intramuscular (IM), intradermal, subcutaneous, intraarticular, intracerebro-spinal, epidural, intraperitoneal, and the like. Furthermore, the compounds of the present invention may be administered by the oral route, in the form of an aqueous suspension or a lyophilized product. Other routes of administration are also acceptable, including topical application to the eye, or administration by inhalation in the form of droplets or a mist.

The dosage forms of the invention may take the form of a powder of microspheres in a vial/ampoule ready for suspension or a pre-made suspension packaged in an injectable ampoule or directly into a syringe ready for human or veterinary use. The suspension medium may be water, 0.6% saline, an oil containing buffers, surfactants, preservatives, which are commonly used by the pharmaceutical artisan to prepare injectable substances or any other substance or composition that does not compromise the physicochemical integrity of the substance in suspension and is suitable for use in the administration of an organism. If it is desired to avoid an initial sudden increase in the content of active ingredient in the medium in the body of the organism to be administered, it is preferable, in the case of a ready-to-use suspension, to use a liquid carrier in which the active ingredient is practically insoluble. In the case where the active substance is partially soluble in the slightly warm but not in the cold liquid carrier, it is preferable from a pharmacological point of view to avoid the formation of precipitates (known as the "caking" effect) by preparing the formulation in the form of a powder of microspheres and a liquid carrier, which are separate from each other, mixed only at the time of injection.

In veterinary applications, diameters of several hundred microns may be used if the desired duration of action is long (e.g. lactation in adult female animals). If it is desired to limit the diameter of the syringe needle for patient comfort, the diameter of the microspheres should be limited to 300 microns and more preferably to 100 microns. Conversely, if the duration of action is short (e.g., 24 hour circadian phase), the diameter of the microspheres can be reduced to 5 microns.

For most human applications (duration of action of active ingredient between 24 hours circadian phase and menstrual cycle), microspheres with a diameter of 5-100 μm are preferred, depending on the active substance/carrier substance combination.

The microspheres can be separated in their diameter during production by known methods, for example by cyclone separators, by air-suction sieving or by sieving in an aqueous medium. In practice, it is sufficient if more than 70% of the microspheres have a diameter in the range 70% to 130% of the specified diameter. If desired, the ideal dissolution profile as determined by the proposed use can be approximated by mixing batches of microspheres having suitably different diameters. In addition, off-specification particles can be reused.

The mechanism of crystallization of solid materials in the presence of vapors containing at least one solvent has not been established. If considered as a solvent, the crystallization process is fully compatible with the conventional principles applied in saturated solutions and in molecular mobility. Some molecular rotational or translational motion may occur, which appears to be dependent on the particular type of solvent used and the vaporization temperature. Hancock et al, "characterization and significance of amorphous state in pharmaceutical systems", J.pharm.Sci., Vol86, No.1, 1-12 (1997). It is clear, however, that the temperature at which crystallization is obtained is well below the glass transition temperature and in fact only corresponds to the temperature required by the solvent vapour pressure.

While not wishing to be bound by any other theory, it is believed that vapor molecules of the solvent may form a micro-agglomeration and micro-accumulation of the solvent on the surface of the particles to be crystallized, thus bringing sufficient energy to the surface molecules of the solid particles forming the organized structure (e.g., crystalline regions).

For the same reason, when a stable polymorph is desired, water molecules, if present in the vapor, can be used to form hydrates.

Once the tissue and/or water absorption process is initiated at the surface, the crystallization process may gradually extend into the interior of the particles without the need for contact with or dissolution in a solvent.

If this is true, there are two facts that appear to show that these micro-agglomerations or molecular agglomerations are extremely small. First, if there is a lot of solvent agglomeration at the particle surface, the solvent will at least partially dissolve it and change its shape. To avoid any partial dissolution, the amount deposited from the vapor must be extremely small.

Second, upon exposure to solvent vapors, the particles inevitably contact each other due to their small size and large number. If there is any surface dissolution of the particles, as would occur if the amount of vapor deposited was not minute, then the particles may tend to stick to each other and clump or agglomerate. This does not occur under the conditions described herein.

Examples

The following examples are presented to illustrate how a substance or mixture of substances can be converted from a metastable state to a more stable crystalline structure according to the method of the invention.

Example 1: 17 beta estradiol microspheres

The substance and other substances are melted/sprayed into droplets and then frozen into microspheres which, when suspended in an aqueous medium, form injectable formulations with extended release.

Microspheres of 17 β estradiol obtained after congealing sprayed droplets of 17 β estradiol at-50 ℃ showed a high proportion of amorphous material.

Heating the microspheres sufficiently crystallizes the amorphous material into an anhydrous polymorph. However, despite complete crystallization, these microspheres are stable at room temperature but unstable when placed in water because the stable polymorph is a hemihydrate (Salole, the physicochemical properties of estradiol, J. -Pharm-Biomed-anal., 1987: 5(7), 635-; Jeslev et al, organic phase analysis, II. two unexpected pseudopolymorphic cases, Arch. Pharm. Chemi. Sci. Ed., 1981, 9, 123- & 130). Thus, in aqueous solution, the species automatically reverts to this more stable polymorph and in so doing reconstitutes its crystallographic alignment into a shape different from that of the microsphere.

When the microspheres were placed in an approximately 7 liter receiver and exposed to 13.5ml of steam of an ethanol and water mixture (50-50) held in a porous cellulosic material at 20-25 ℃ for 24 hours, the initial amorphous microspheres crystallized directly to the stable hemihydrate polymorph in the presence of steam and were stable when re-placed in water thereafter.

To evaluate the stability of the crystallized 17 β estradiol microspheres, the microspheres were placed in an aqueous solution at 40 ℃ and observed by optical microscopy after 274 days. Thus, the stability of the microspheres in the hemihydrate-containing form in water can be verified using light microscopy.

The residual ethanol in the microspheres is less than 0.01 percent.

Example 2: testosterone microspheres

Testosterone has been reported to have several polymorphs, two of which are stable in water in the form of hydrates (Frokjaer et al, differential scanning calorimetry application in determining the solubility of metastable drugs, Arch. pharm. Chemi. Sci. Ed., 2, 1974, 50-59; Frokjaer et al, dissolution behavior involving the same phase transition of metastable drugs, Arch. pharm. Chemi. Sci. Ed., 2, 1974, 79-54; Thakkar et al, micellar solubilization of testosterone III, dissolution behavior of testosterone in aqueous solutions of selected surfactants, J.pharm. Sci., Vol 58, No.1, 68-71).

Testosterone microspheres prepared immediately by the same spray/congealing procedure as 17 β estradiol were shown to contain the same high level of amorphous material. The microspheres were heated at 117 ℃ for 23 hours and they crystallized to the anhydrous polymorph similar to that seen in the commercial raw material. However, when these microspheres are placed in water, the anhydrous polymorph spontaneously converts to a hydrated structure, a transformation that causes the microspheres to lose their shape.

In contrast, when these microspheres were placed in an approximately 7 liter receiver and exposed to 40ml of steam of a mixture of acetone and water (80-20) held in a porous cellulosic material at 20-25 ℃ for 24 hours, the original amorphous microspheres crystallized directly to the stable hydrate polymorph described above in the presence of steam. These crystalline particles appear to exhibit storage stability when placed in water.

To evaluate the stability of testosterone microspheres, the microspheres were placed in an aqueous solution at 40 ℃ and observed by an optical microscope after 54 days. For comparison, non-crystalline testosterone microspheres (melt-congealing only) were also placed in the aqueous solution and observed after 40 days. As can be seen by comparing the optical micrographs, the stability in water of microspheres comprising the hydrate polymorph is evident compared to non-crystalline microspheres.

The residual ethanol in the microspheres is less than 0.01 percent.

Example 3: progesterone microspheres

Testosterone microspheres prepared immediately by the same spray/congeal process as above were shown to contain polymorph I and II crystals. Progesterone has been reported to be free of hydrate polymorphs.

However, when these microspheres were placed in an approximately 7 liter receiver and exposed to 13.5ml of steam of a mixture of ethanol and water (50-50) held in a porous cellulosic material at 20-25 ℃ for 4 hours, the initial amorphous microspheres crystallized directly to the stable polymorph I in the presence of steam and were stable when thereafter placed back in water.

To evaluate the stability of the crystallized progesterone microspheres, the microspheres were placed in an aqueous solution at 40 ℃ and observed by optical microscopy after 187 days.

It should also be noted that in the case of progesterone, the use of solvent vapor also causes the conversion of polymorph II, present in the structural mixture obtained after spray-congealing, into polymorph I, as can be observed by DSC.

Furthermore, in the case of progesterone, exposure to solvent vapors can also be successfully achieved by using a flow system. The microspheres were placed in a 1.6 liter sealed crystallization chamber rotating at 5 rpm and contacted with ethanol vapor for 24 hours.

In both experiments, the residual ethanol in the microspheres was less than 0.01%.

Example 4: asimidazole microspheres

To demonstrate the success of the process of the present invention in forming stable crystals of organic compounds other than steroids and sterols, astemizole microspheres were subjected to solvent vapor treatment.

Astemizole microspheres prepared immediately by the same spray/congealing procedure as above also showed high content of amorphous material. However, when 100mg of microspheres were placed in an approximately 0.5 liter receiver and exposed to 0.5ml of ethyl acetate vapor held in a porous cellulosic material at 30 ℃ for 24 hours, the original amorphous microspheres crystallized directly to the stable polymorph in the presence of the vapor. Similar results were obtained in another experiment using acetone.

To evaluate the stability of astemizole microspheres, the microspheres were placed in an aqueous solution at 40 ℃ and observed by optical microscopy after 76 days.

Example 5: asimidazole pellet

In the case of astemizole pellets, pellets prepared immediately by congealing the molten starting material at-50 ℃ were shown to contain a high content of amorphous material. However, exposure of 150mg astemizole pellets in an approximately 0.5 liter receiver to a steam of ethyl acetate contained in a porous cellulosic material at 30 ℃ for 24 hours resulted in crystallization of the pellets without any change to the shape of the granules. Similar results were obtained in another experiment using acetone.

Example 6: cholesterol microsphere

The cholesterol microspheres prepared immediately by spraying/congealing the same as above showed to contain amorphous material. Cholesterol has been reported to have no polymorph.

When 100mg of the microspheres were placed in an approximately 0.5 liter receiver and exposed to 1ml of acetic acid vapor held in a porous cellulosic material at 30 ℃ for 8 hours, the original amorphous microspheres were completely crystallized.

Crystallization of substance mixtures

Mixing different substances in melt congealed component particles can provide important benefits. Which comprises the following steps: adjusting dissolution rate, lowering melting point, diluting active components, improving chemical stability of main components, etc. The ability to crystallize particles composed of a mixture of substances therefore significantly increases the range of applications of the melted congealed solid in hygiene and other fields.

Mixtures of many substances can melt and congeal. However, since the components have different particle characteristics, the mixture tends to form a complex metastable structure when congealed and it is possible to crystallize them in addition to the eutectic mixture, since one of the substances may melt before the transition point temperature is reached.

As mentioned above, particles comprising a plurality of allotropic organic compounds are also suitable for use in the solid state crystallization of the present invention. The crystallization is complete and the resulting granules are stable at typical storage and use temperatures, in both water and dry atmospheres.

Example 7: microspheres of a mixture of 40% 17 beta estradiol and 60% cholesterol

The microspheres of the mixture are obtained by melting the components together and if pure substances they are sprayed into droplets and congealed into microspheres. Initially, they were shown to contain high levels of amorphous material.

When these microspheres were placed in an approximately 7 liter receiver and exposed to 8ml of ethanol vapor held in a porous cellulosic material at 30 ℃ for 24 hours, the original amorphous microspheres were completely crystallized in the presence of the vapor.

The microspheres were vacuum dried at 60 ℃ for 24 hours and residual ethanol in the microspheres was less than 0.01%.

To evaluate the stability of the microspheres, the non-crystalline microspheres of the invention (melt-congealing only) and the microspheres were placed in an aqueous solution at 40 ℃ and observed by optical microscopy after 82 days, respectively. As observed by optical microscopy, the crystalline microspheres of the present invention remain stable when placed in water, whereas non-crystalline microspheres do not.

In vivo stability

In the case of slow release injections or implants, it is important that the particles retain their physical integrity after administration to the patient in order to ensure the required release rate and reproducibility of action. Thus, the in vivo stability of the particles described in the above examples was checked with male new zealand rabbits.

Light microscopy photographs taken 1, 4, 7 and 14 days after intramuscular injection showed that the microspheres maintained their integrity until final dissolution. For comparison, the uncrystallized microspheres were also administered by injection. Their optical micrographs show that these microspheres become non-spherical in shape.

Example 8: microspheres of a mixture of 10% 17 beta estradiol and 90% cholesterol

Microspheres of this mixture were obtained by melting the components together, spraying them into droplets and congealing into microspheres as described in the above examples. Initially, they were shown to contain high levels of amorphous material.

When these microspheres were placed in an approximately 7.0 liter receiver and exposed to 8ml of ethanol vapor stored in a porous cellulosic material at 5 ℃ for 24 hours, the original amorphous microspheres were completely crystallized in the presence of the vapor.

The microspheres were subsequently vacuum dried at 60 ℃ for 24 hours with less than 0.01% ethanol remaining in the microspheres.

To evaluate the stability of the crystalline microspheres, they were placed in an aqueous solution at 40 ℃ and observed by an optical microscope after 141 days.

Example 9: microspheres of a mixture of 95.2% progesterone and 4.8% 17 β estradiol

Microspheres of this mixture were obtained by melting the components together, spraying them into droplets and congealing into microspheres as described in the above examples. Initially, they were shown to contain high levels of amorphous material.

When the microspheres were placed in an approximately 7 liter receiver and exposed to 2ml of ethanol vapor stored in a porous cellulosic material at 20-25 ℃ for 24 hours, the original amorphous microspheres were completely crystallized in the presence of the vapor.

The microspheres were subsequently vacuum dried at 60 ℃ for 24 hours with less than 0.01% ethanol remaining in the microspheres.

Example 10: microspheres of a mixture of 60% progesterone and 40% cholesterol

Microspheres of this mixture were obtained by melting the components together, spraying them into droplets and congealing into microspheres as described in the above examples. Initially, they were shown to contain high levels of amorphous material.

When the microspheres were placed in an approximately 7 liter receiver and exposed to 2ml of ethanol vapor held in a porous cellulosic material at 30 ℃ for 24 hours, the original amorphous microspheres were completely crystallized in the presence of the vapor.

The microspheres were subsequently vacuum dried at 60 ℃ for 24 hours with less than 0.01% ethanol remaining in the microspheres.

It is thus clear that the process of the present invention is broadly applicable to the formation of stable crystalline particles, microspheres and pellets of various organic compounds and mixtures that retain their shape in aqueous solution. The method of the invention should therefore have important applications in the manufacture of medicaments and pharmaceutical compositions, particularly when the treatment requires administration of the medicament in the form of a sustained release formulation.

While certain embodiments of the present invention have been illustrated and described herein, it will be obvious to those skilled in the art that various changes can be made in the crystallization process described without departing from the spirit and scope of the invention.

Claims (7)

1. A storage-stable, uniformly shaped particle comprised of an allotropic organic compound having uniform crystalline characteristics and a multiple crystalline domain structure, which organic compound retains said crystalline characteristics and said particle retains said uniform shape when stored in an aqueous medium for at least about one month.

2. The particle of claim 1, wherein the desired crystalline form of at least one of the allotropic organic compounds is a hydrate.

3. The particles of claim 1, wherein at least one of said allotropic organic compounds is a steroid or a sterol.

4. The particles of claim 3 wherein the steroid or sterol is selected from the group consisting of 17- β -estradiol, estrogen, testosterone, progesterone, cholesterol and mixtures thereof.

5. The particle of claim 1, wherein said at least one said allotropic organic compound is astemizole, cisapride, or oxazimide.

6. The particles of claim 1 wherein one or more of said compounds is a steroid or a sterol and one or more of said compounds is selected from the group consisting of oxamidines, nifedipine, astemizole and cisapride.

7. The particles of claim 1, wherein one of the allotropic organic compounds is cholesterol.