Process for preparing water-soluble micronized substances

The present invention relates to a process for obtaining micronized, water-soluble substances that can be produced, stored and used, while maintaining their aerodynamic properties , required for the inhalation of such substances and having improved physico-chemical properties, in the dry state, thereby facilitating the technical manipulation and significant increase of the medical value of the substances.

During the last few years, there have been frequent demonstrations that the proper selection of the appropriate crystalline modification can significantly influence the clinical results of a given chemical quantity. The chemical and physical stability of a solid compound, in a particular dosage form, can be modified by presenting the substance in the form of a crystal, as appropriate. There is too little accessible information about the role of polymorphism and crystal in solid dosage form and powder technology. However, it is obvious that the proper selection of the most suitable crystalline modification, resulting either from polymorphic differences or as a result of the formation of the solvated complex of both water-soluble and less water-soluble substances, such as theophylline, may it often significantly increases the medical value of a given drug, in a particular dosage form. There are only a few accessible reports that predict the consequence of a crystallization procedure, if, for example, the substance could be involved in various polymorphic or pseudopolymorphic forms. Solid state transformations may also occur during mechanical treatment, for example, by micronization and by pressing, during tableting. While some generalizations may be made regarding the influence of structural changes on the tendency of a particular compound to exhibit polymorphism or other phenomena, a full understanding of this problem requires further research. Often "trial and error" approaches are used to promote a successful formulation of a drug. It is necessary to establish the conditions under which different forms of a substance can be transformed into a single form thus eliminating the differences in solid state properties and subsequently the different physico-chemical properties.

E.Shefter and T.Higuchi measured the relative dissolution rates of several solvated and unsolvated crystalline forms of important pharmaceutical substances,

J.Pharm.Sci., 52 (8), (1963), 781 -91.

L. Van Campen, G. Zografi and JT Carstensen present, in a review article, a study of evaluation of hydroscopicity for solid pharmaceutical substances, ln.J.Pharmaceut.5, (1980), 1-18.

C. Ahleck and G. Zografi describe the molecular basis of humidity, on the physical and chemical stability of solid state drugs, Int. J. Pharmaceut., 62, (1990), 87-95.

M. Otsuka et al. calculated the hydration data, using various kinetic models, of the solid state, for theophylline anhydrous powder. , J. Pharm. Pharmacol, 42, (1990), 606610.

Hak-Kim Chan and Igor Gonda examined the properties of the breathable crystals of chromoglic acid, using various methods, J.Pharm. Sci., 78 (2), (1989), 176-80.

a clearer discussion of the factors referring to pharmaceutical preformulations and the physico-chemical properties of medicinal substances is given by JIWells in: Physico-chemical Properties In Pharmaceutical Preformulations: of Substances

Medicaments, John Wiley and Sons, New York (1988) (see the particular chapter on polymorphism, pp. 86-91).

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A process for producing spherical particles of pancreatin is known which consists of rotating the wet mass of pancreatin with a solvent around a first axis and stimulating the reduction of the size of the soft particles with rotary knives around a third axis while a part it is removed from the solvent.

The object of the invention is to provide a process for micronized, 50 water-soluble substances that can be produced, stored and used while maintaining the aerodynamic properties required for the inhalation of such substances, thereby reducing waste water from micronized substances, conditioning the respective dry substances, micronized with a solvent and, finally, removing the residual solvent from the substances.

It is an object of the present invention to provide a safe process, wherein the desired polymorphic form 55 can be conveniently and reproducibly prepared.

The process for obtaining micronized, water-soluble substances, which, for the purpose of obtaining particles smaller than 100 μΓΠ that can be produced, stored and used, while maintaining the aerodynamic properties required for the inhalation of such substances, comprises the following phase: 60

a) reducing, if necessary, the waste water from the micronized substance, by optional drying, at a high temperature and / or from:

b) conditioning the dry micronized substance with a solvent selected from organic alcohols, ketones, esters, acetonitrile or other pharmaceutically acceptable solvents, preferably in vapor phase or, in an inert gas, containing solvent vapors, gas which optionally 65 is nitrogen ; and

c) disposal of the residual solvent by storage in a dry place, such as vacuum, or by purging with an inert gas, gas which, optionally, is nitrogen.

The solvents used in conditioning step b) are alcohols, ketones, organic esters, acetonitrile and the like, most preferably lower alcohols such as methanol, ethanol, 70 n-propanol, isopropanol; lower ketones such as acetone, methylethylketone; ethyl acetate, preferably in the vapor phase.

According to a preferred embodiment, the conditioning step b) is carried out in an inert gas, containing solvent vapors.

The inert gas used in step c) and optionally in step b) is preferably nitrogen. 75

Preferred substances to which the invention is to be applied are carbohydrates, amino acids and medicines.

Carbohydrates, such as lactose, glucose, fructose, galactose, trehalose, sucrose, maltose, xylitol, mannitol, myoinositol, and the like, and amino acids, such as alanine, betaine, and the like, are often used as additives. In pharmaceutical compositions 80, for example, as additives in certain inhalation formulations.

Terbutaline sulfate, sabultamol sulfate, phenoterol hydrobromide and bambuterol hydrochloride are β-agonists₂ - High-selectivity adrenergics, which have a bronchospasmolytic effect and are effective in the treatment of obstructive, reversible, lung diseases, of various origins, especially of asthmatic sufferings. Disodium chromoglycate 85 (DSCG) has been used for many years as a prophylactic agent in the treatment of allergic bronchial asthma.

The invention will be described, using lactose, terbutaline sulfate and sabutanol sulfate, as examples. The phenomenon of solvent formation and polymorphism is clearly recognized in the literature, in preformulation studies, in the design phase for 90 new drugs in solid state, for example US Pharmacopoeia recognizes

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Many substances exist in various polymorphic (pseudopolymorphic) forms and as many metastable solvates with variable physical composition and properties, such as mass density and hydroscopicity. Several transformations between these polymers can occur at different speeds. These effects occur when crystalline substances have been activated by various processes, such as milling, freeze drying, micronization and recrystallization, to produce regions with a partially amorphous structure. Often the substances will be obtained in an amorphous state or in a metastable crystalline state when dried by spray, freeze, rapid cooling of the solvent, or when controlled precipitation using both crystalline and crystalline forms can be prepared. amorphous. The use of an amorphous or crystalline, metastable form is often limited due to its thermodynamic instability. Therefore, it is desirable to convert the amorphous form or the metastable crystalline form into the more stable crystalline state. The present invention deals with such physical and chemical changes, or more importantly, their anticipation and the means by which these solid state phenomena can be manipulated.

After recrystallization (or after spray drying / freeze drying), the substance must be micronized to the final particle size, which is required, for example, for inhalation. The particles should be less than 1OO pm and preferably less than 10 pm. For crystalline substances, the micronize stage seems to give an amorphous outer layer of the particle, making the particle more sensitive to moisture.

It is an object of this invention to be able to provide, in a stable manner, a crystalline form of certain water-soluble substances that can be produced, stored and used, while maintaining their aerodynamic properties and characteristics (particle size, particle shape, hydroscopicity, etc.) required for inhalation of such substances. The particle size of the micronized substance is the same, before and after the conditioning step, as measured with different instruments such as Malvern Master Sizer, Culter Counter or a microscope.

Conditioning of the substance probably rearranges the outer layer of crystals or the amorphous substance, giving a more stable and less hydroscopic product.

Three embodiments of the invention are given below.

Example 1. 3.6 kg of micronized terbutaline sulfate is dried in a stainless steel column, 200 mm in diameter, at 9 ° C, under vacuum, for 23 hours. The dry matter is cooled to about 3 ° C and the pressure is normalized with nitrogen gas saturated with ethanol. Through the 200 mm diameter column, gas ethanol saturated with ethanol, with a flow rate of 70 ml / min, for 60 h is passed to condition the substance. During this time, the column is reversed several times. The residual solvent is removed by purging with nitrogen gas for 2 hours and the product, about 3.5 kg, is packed in double plastic bags with a drying agent between the bags.

Example 2. 1 g of micronized salbutamol sulfate is kept at room temperature for 24 hours in a closed vessel containing a beaker filled with ethanol. The sample is removed and stored in a completely dry environment overnight to remove traces of ethanol.

It is necessary to introduce agitation or reversal of the substance, when the conditioning is done on a large scale.

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Example 3. 1 g of spray-dried amorphous lactose is treated as in Example 2. The retention time in ethanol-saturated vapors is 1QO h. After removal of the residual ethanol, the sample is subjected to calorimetric analysis.

In some situations, it has been possible to use infrared spectroscopy to study the transformation of an amorphous or partially crystalline form into a stable crystalline form. Other accessible methods include BET adsorption of gas, X-ray powder diffraction, microcalorimetry and differential calorimetric analysis (DSC). BET gas adsorption and microcalorimetry have been found to be the best methods for distinguishing different forms of test compounds.

Test results

The surface area measured by determining the amount of a gas (nitrogen), which is absorbed as a single layer of molecules, is formed as a monomolecular layer (Flowsorb II 2300, Micromeritics Co, USA). Area h.

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<td rowspan="2">Micronized substance Conditional substance (m²/ G)</td><td colspan="2">Unconditional substance</td>

<td>(m²/ G)</td><td>(m²/ G)</td>

<td>Terbutaline sulphate 11 x 12.5</td><td> 3</td><td> 7-9</td>

<td>Salbutamol sulphate 8.4</td><td> 3</td><td> 5,9</td>

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With the low surface area, obtained when the micronized substance was stored at high humidity, the mass of the substance has a great tendency to become crowded during storage, which makes the substance very difficult to handle technically, in the manufacture of different formulations needed.

The interactions between certain substances and water vapor have also been studied by microcalorimetry. When these substances are subjected to water treatment, in the vapor phase they give up heat in a highly cooperative process. However, this moisture-induced transition phase is not observed in conditioned substances. Thus, the conditioning process transforms the substance into a more stable form, which is less sensitive to moisture.

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Comparison of the heat yielded by the unconditioned and the conditioned substances when subjected to water vapor. The experiments are performed with Thermal Activity Monitor 2277 (Thermometrics, Sweden).

<td>Relative humidity (%)</td><td colspan="2">Heat (J / g) Unconditional substance</td>

<td>Condensed substance Terbutaline sulphate</td><td></td><td></td>

<td> 58</td><td> 3,6</td><td> 0,1</td>

<td> 75</td><td> 6,2</td><td> 0,1</td>

<td>Salbutamol sulphate</td><td> 6-8</td><td> 0,1</td>

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When spray dried lactose was conditioned in ethanol vapors for 1OO h at room temperature, the yielded energy was &lt;0.1 J / g, while unconditional lactose lost 40 - 44 J / g when lactose is subject to water vapor.

The stability of the particles that have been conditioned is surprising and will greatly increase the flexibility of the use of the substance for different formulations.