Method of obtaining water-soluble micronised substances

The present invention relates to a process for the production of water-soluble, micronized substances that maintain the aerodynamic properties needed for inhalation during preparation, storage and use, which substances have improved physicochemical properties in the dry state, which facilitates their technical processing and significantly increases their medical value.

Over the past few years it has often been shown that the right choice of the most appropriate crystal modification can significantly affect the clinical results of a particular chemical. The physical and chemical stability of the solid compound in a particular dosage form can be modified using the substance in the appropriate crystallization form. Little information is available about the role of polymorphism in preserving crystals in the technological process of obtaining solid dosage forms and powders. However, it is obvious that the right choice of the most useful crystal form, resulting from polymorphic differences or resulting from the formation of a solvate, both water-soluble and less water-soluble substances, such as theophylline, often significantly increases the medical value of a given drug in a given dosage form. Little information is available

168 232 to predict the result of crystallization, if e.g. the substance can exist in different polymorphic or pseudopolymorphic forms. Solid state transformations can also occur during machining, e.g. micronization or pressing during tabletting. Although some generalizations can be made about the effects of structural modifications on the propensity of a selected compound to exhibit polymorphism or other phenomena, a complete understanding of this problem requires further research. Often, a trial and error method is used to obtain the desired formulation of a given drug. It is necessary to establish the conditions under which different forms of a substance can be converted into one form in order to eliminate differences in solid state properties and the resulting differences in physicochemical properties.

E. Shefter and T. Higuchi described in J. Pharm.Sci., 52 (8), (1963), 781-91, the relative dissolution rates of various crystalline, solvated and unsolvated forms of important pharmaceuticals.

L. van Campen, G. Zografi and JT Carstensen presented in a review article in Int. J. Pharmaceut., 5, (1980), 1-18 approach to testing hygroscopicity of solid pharmaceuticals.

C. Ahlneck and C. Zografi described the molecular basis of the effect of moisture on the physical and chemical stability of solid-state drugs (Int. J. Pharmaceut., 62 (1990), 87-95).

M. Otsuka et al. Presented in J. Pharm. Pharmacol., 42, (1990), 606-610), calculations regarding hydration of anhydrous powdered theophylline using various kinetic models.

Hak-Kim Chan and Igor Gonda investigated the properties of the breathable crystals of 4,4'dioxo-5,5 '- (2-hydroxytrimethylene dioxy) -di- (4H-chromene-2-carboxylic acid) (cromaglycic acid) using different methods (J. Pharm. Sei., 78 (2), (1989), 176-80).

A more comprehensive review of factors affecting pharmaceutical preformulations and physicochemical properties of drug substances was presented by JI Wells in Pharmaceutical Preformulation: The Physicochemical Properties of Drug Substances, John Wiley and Sons, New York (1988), in particular in the chapter on polymorphism, pp. 86- 91.

The method of producing water-soluble, micronized substances that maintain the aerodynamic properties needed for inhalation by means of optionally reducing the amount of residual water in the micronised substance, optionally at elevated temperature and / or under reduced pressure, during the preparation, storage and use, according to the invention, in dry above, the micronized material is further conditioned with a solvent and residual solvent is removed by holding the substance in a dry place, preferably obtained by reducing pressure, or by passing an inert gas. Solvents used in the conditioning step are organic alcohols, ketones, esters, acetonitrile, etc., most preferably lower alcohols such as methanol, ethanol, n-propanol and isopropanol; lower ketones such as acetone and methyl ethyl ketone; ethyl acetate, preferably in gaseous form.

According to one preferred embodiment of the invention, the conditioning is carried out in an inert gas containing solvent vapors.

The inert gas used in the solvent removal step and optionally in the conditioning step is preferably nitrogen.

Carbohydrates, amino acids and drugs are preferred substances for which the method of the invention may be used.

Carbohydrates such as lactose, glucose, fructose, galactose, trehalose, sucrose, maltose, xylitol, mannitol, myoinosito, etc., and amino acids such as alanine, betaine, etc., are often used as additives in pharmaceutical compositions, e.g. as additives in inhalation preparations.

Terbutaline sulfate, salbutamol sulfate, and Bambuterol hydrobromide are highly selective P2-adrenergic agonists that utilize the anti-bronchoconstrictor effect and are effective in the treatment of reversible obstructive pulmonary diseases of various origins, in particular asthmatic diseases. Disodium chromoglycan [DSCG, disodium salt of 4,4'-dioxo-5,5 '- (2-hydroxytrimethylene dioxy) -di (4-chromene-2-carboxylic acid)] has been used as a prophylactic agent for preventing allergic bronchial asthma for many years. .

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The invention is described with reference to examples, to lactose, terbutaline sulfate and salbutamol sulfate. The phenomenon of solvate formation and polymorphism are well known in the literature on research on pre-formulation in the phase of research of new solid state drugs, e.g. the US Pharmacopoeia lists> 90 drug hydrates.

Many substances occur in different polymorphic (pseudopolymorphic) varieties and in the form of different metastable solvates with different composition and physical properties, such as bulk density and hygroscopicity. Different transformations can occur between such polymorphs at different speeds. They can be obtained when activating crystalline substances in various processes, such as comminution, lyophilization, micronization or recrystallization to obtain areas with a partially amorphous structure. Substances are often obtained in amorphous form or as a metastable form when spray drying, lyophilization, rapid solvent quenching are used, or when controlled precipitation is used, which can result in both crystalline and amorphous forms. The use of amorphous or in the form of metastable crystals is often limited due to the thermodynamic instability of such varieties. It is therefore desirable to transform the amorphous or metastable crystals into a more stable crystalline state. The object of the method of the invention is to bring about such physical and chemical changes, or more importantly, to anticipate such changes and the means by which these solid state phenomena can be obtained.

After recrystallization (or after spray drying or freeze drying) the substance must be micronized to obtain the particle size required e.g. for inhalation. The particles should be smaller than 100 gm, or smaller than 10 pm. In the case of crystallization, it seems that microeisation gives an amorphous outer layer of particles, as a result of which the particles are more sensitive to moisture.

The subject of the invention is a reliable method for obtaining the crystalline form of various water-soluble substances that can be produced, stored and used with aerodynamic properties and properties (particle size, particle form Cigroskoyness, etc.) required for inhalation. The particle size of the micronized substances is the same before and after conditioning, according to the results of measurements made with different apparatus such as Malvern Master Sizer, sorter or microscope.

Conditioning the substance probably transforms the outer layer of crystals or amorphous substance, resulting in a more stable and less hygroscopic product.

In some cases, it is possible to use infrared spectroscopy to study the conversion of an amorphous or partially crystalline form into a stable crystalline form. Other available methods are gas adsorption (BET), X-ray powder diffraction, microcalorimetry and differential scanning calorimetry (DSC). BET gas adsorption and microcalorimetry were found to be the best methods for distinguishing different forms of test compounds.

Test results. The surface area was measured by determining the amount of gas (nitrogen) adsorbed as a single layer of particles forming a single-particle layer on the sample using a gas absorption device called Flowsorb II2300, ex Micromeritics Co., St. Ser. America. The specific surface after leaving the sample for 24 hours in high humidity conditions.

<td>Substance</td><td>Substance</td><td>Substance</td><td></td>

<td>smlkroeisowaea (m²/ G)</td><td>eiekoedrnjoeowaea (m²/ G)</td><td>co-ordination (m²/ G)</td><td></td>

<td>Sulfate also 11-12.5</td><td> &lt;3</td><td> 7-9</td><td></td>

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

A substance with a smaller specific surface, obtained by storage after micro-emission in conditions of high humidity, has a strong tendency to caking

168 232 during storage. This hinders its technical processing during the production of various preparations needed.

The effects of water vapor on various substances were also tested with a microcalorimeter. When these substances are exposed to water in the gas phase, heat is released in a highly cooperative process. However, the moisture-induced phase transition is not observed for the conditioned substance. Therefore, the conditioning process transforms the substance into its more stable form, less sensitive to moisture.

The following is a comparison of the amount of heat released for unconditioned and conditioned substances treated with steam. The experiments were performed using a Thermal Activity Monitor 2277 (Thermometries, Sweden).

<td colspan="3">Heat (J / g)</td>

<td>Relative humidity</td><td>Non-conditional substance</td><td>Conditioned substance</td>

<td>Terbutaline sulfate</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 sulfate</td><td></td><td></td>

<td> 75</td><td> 6-8</td><td> 0,1</td>

When spray-dried lactose was conditioned in ethanol vapors for 100 hours at room temperature, the amount of released energy after administration on steam was &lt;0.1 J / g, while for unconditioned lactose the energy loss was 40-44 J / g.

The stability of the conditioned particles was amazing. This significantly increases the flexibility of applying the substance to various preparations.

The invention is illustrated by the following examples.

Example 1. 3.6 kg of micronised terbutaline sulfate were dried in a stainless steel column 200 mm in diameter at 90 ° C under reduced pressure for 23 hours. The dried material was cooled to about 30 ° C and the pressure was brought to normal with nitrogen saturated ethanol. 70 ml / min of ethanol-saturated nitrogen was bubbled through the above 200 ml column for 60 hours, thus conditioning the substance. During this time, the column was inverted several times. Residual solvent was removed by bubbling nitrogen for 2 hours, after which the product (about 3.5 kg) was packed in double plastic bags containing a desiccant between the walls of the bags.

Example II In this experiment, 1 g of micronized sulbutamol sulfate was left for 24 hours at room temperature in a closed vessel containing a beaker with ethanol. The sample was then removed and left in a completely dry environment overnight to remove residual ethanol. The sample was then analyzed (results given above).

For large-scale conditioning, it is necessary to use mixing or shaking of the substance in the drums.

Example III. An aliquot of 1 g of spray-dried amorphous lactose was subjected to the treatment described in Example 2. The retention time in an environment saturated with ethanol vapors was 100 hours. After removing residual ethanol, the sample was subjected to calorimetric analysis (results given above).

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