Conditioned water soluble substances

Field of the Invention

0001The present invention relates to water-soluble micronised substances, which can be produced, stored and used while maintaining the aerodynamic properties required for inhalation of such substances and which have improved physicochemical properties in the dry state, thereby facilitating the technical handling and significantly increasing the medical value of the substances.

Background of the Invention

0002During the past few years, there have been frequent demonstrations of the fact that the appropriate selection of the most suitable crystalline modification significantly can influence the clinical results of a given chemical entity. The chemical and physical stability of a solid compound in a particular dosage form can be modified by presenting the substance in the appropriate crystal form. Little information is available on the role of polymorphism and crystal habit in solid dosage form and powder technology. It is, however, apparent that the appropriate selection of the most suitable crystalline modification, whether arising from polymorphic differences of as a result of solvate complex formation of both water-soluble substances and less water-soluble substances such as theophylline, often significantly can increase the medical value of a given drug in a particular dosage form. There are only a few statements available to predict the outcome of a crystallisation procedure if e.g. the substance could be involved in different polymorphic or pseudopolymorphic forms. Solid-state transformations may also occur during mechanical treatment, e.g. micronisation and by pressure during tableting. While a few generalisations can be made concerning the influence of structural modifications on the tendency of a chosen compound to exhibit polymorphism or other phenomena, a complete understanding of this problem awaits further research. Often "trial and error" approaches are used to develop a successful formulation of a drug. It is necessary to establish the conditions whereby different forms of a substance might be converted to a single form thus eliminating differences in solid-state properties and subsequent different physico-chemical properties.

0003E. Shefter and T. Higuchi have measured the relative rates of dissolution of several crystalline solvated and non-solvated forms of important pharmaceuticals, J. Pharm. Sci., 52 (8), (1963), 781-91.

0004L. van Campen, G. Zografi and J.T. Carstensen give in a review article an approach to the evaluation of hygroscopicity for pharmaceutical solids, Int. J. Pharmceut. 5, (1980), 1-18.

0005C. Ahlnech and G. Zografi describe the molecular basis of moisture on the physical and chemical stability of drugs in the solid state, Int. J. Pharmceut., 62, (1990), 87-95.

0006M. Otsuka et al. have calculated hydration data using various solid-state kinetic models for theophylline anhydrate powder, J. Pharm. Pharmacol., 42, (1990), 606-610.

0007Hak-Kim Chan and Igor Gonda have examined the properties of respirable crystals of cromoglycic acid by using different methods, J. Pharm. Sci., 78 (2), (1989), 176-80.

0008A more comprehensive discussion of factors relating to pharmaceutical preformulations and the physicochemical properties of drug substances is given by J.I. Wells in Pharmaceutical Preformulation: The Physicochemical Properties of Drug Substances, John Wiley & Sons, New York (1988). See particularly the chapter about polymorphism pp 86-91.

0009US 4, 866,051 discloses pharmaceutical powder compositions comprising micronised beclomethasone dipropionate monohydrate which are said to be stable after prolonged storage.

Brief description of the Invention

0010The object of the invention is to provide water-soluble micronised substances, which can be produced, stored and used while maintaining the aerodynamic properties required for inhalation of such substances, whereby reducing the residual water from the micronised substances, conditioning said dried, micronised substances with a solvent and finally eliminating residual solvent from the substances.

Detailed description of the Invention

0011In a first aspect the invention provides a water soluble micronised substance having a particle size of less than 10 µm in a stable crystalline form, wherein the particle size of the micronised substance is identical before and after conditioning said micronised substance with a solvent, characterised in that the substance is a β₂-adrenergic agonist selected from terbutaline or salbutamol sulphate.

0012Preferably the terbutaline sulphate of the invention has a surface area when measured by BET nitrogen adsorption using a Flowsorb II 2300 of from 7 to 9 m²/g after having been standing in high humidity for 24 hours.

0013Preferably the terbutaline sulphate has a heat of evolution when subjected to water vapour and when measured using a Thermometic 2277 Thermal Activity Monitor of 0.1 J/g.

0014Preferably the salbutamol sulphate according to the invention has a surface area when measured by BET nitrogen using a Flowsorb II 2300 of 5.9m²/g after having been standing in high humidity for 24 hours.

0015Preferably the salbutamol sulphate according to the invention has a heat of evolution when subjected to water vapour and when measure using a Thermometric 2277 Thermal Activity Monitor of 0.1 J/G.

0016The water soluble micronised substances of the present invention can be obtained by a reliable process, where the desired polymorphic form can be conveniently and reproducibly prepared. It relates to a three-step procedure: - <ul id="ul0001" list-style="none" compact="compact"><li>a. reducing, if necessary, the residual water from the micronised substance by drying optionally at an elevated temperature and/or vacuum.</li><li>b. conditioning said dried micronised substance with a solvent, and</li><li>c. eliminating the residual solvent by storing the substance in a dry place, such as vacuum, or by purging with an inert gas.</li></ul>

0017The solvents used in the conditioning step b) are organic alcohols, ketones, esters, acetonitrile and the like, most preferably lower alcohols like methanol, ethanol, n-propanol, isopropanol; lower ketones like acetone, methylethylketone, ethylacetate, preferably in the vapour phase.

0018According the one preferred embodiment the conditioning step b) is carried out in an inert gas containing solvent vapour.

0019The inert gas used in step c) and optionally in step b) is preferably nitrogen.

0020The preferred substances on which the invention is to be applied are terbutaline sulphate and salbutamol sulphate.

0021Terbutaline sulphate and salbutamol sulphate, are highly selective β₂-adrenergic agonist having bronchospasmolytic effect and are effective in the treatment of reversible obstructive lung ailments of various genesis, particularly asthmatic conditions. Disodium chromoglycate (DSCG) has been used as a prophylactic agent in the treatment of allergic bronchial asthma for many years.

0022The invention will be described by using terbutaline sulphate and salbutamol sulphate. The phenomena of solvate formation and polymorphism are well recognised in the literature in the preformulation studies in the development phase for new drugs in the solid state. e.g. the US Pharmacopoeia recognises &lt;90 drug hydrates!

0023Many substances exist in different polymorphs (pseudopolymorphs) and several metastable solvates with variable composition and physical properties like bulk density and hygroscopicity. Several transformations between these polymorphs may occur at different velocity. These effects are operating when crystalline substances have been activated by various processes such as grinding, freeze drying, micronisation or recrystallisation to produce regions of partial amorphous structure. The substances often will be obtained in an amorphous state or a metastable crystalline form when spray drying, freeze drying, rapid solvent quenching or when using controlled precipitation where both crystalline and amorphous forms can be prepared. The use of an amorphous form or a metastable crystalline form is often limited due to its thermodynamic instability. It is therefore a desire to convert the amorphous form or the metastable crystalline state. The present invention deals with such physical and chemical changes, or more importantly, to anticipate them and the means by which these solid-state phenomena can be handled.

0024After recrystallisation (or after spray drying/freeze drying) the substance has to be micronised to the final particle size required for e.g. inhalation. The particles is less than 10 µm. For crystalline substances, the micronisation step seems to give an amorphous outer layer of the particle making the particle more sensitive to moisture.

0025It is an object of this invention to be able to reliably provide a crystalline form of certain water-soluble substances, which can be produced, stored and used, while maintaining the aerodynamic properties and specifications (particle size, particle form, hydroscopicity etc.) required for inhalation of such substances. The particle size of the micronised substances is identical before and after the conditioning step as measured by different instruments like Malvern Master Sizer, culter counter or a microscope.

0026The condition of the substance probably rearrange the outer layer of the crystals of the amorphous substance giving a more stable and less hygroscopic product.

0027In some instances it has been possible to use infrared spectroscopy in order to study the conversion of an amorphous form or a partly crystalline form into a stable crystalline form. Other methods available include BET gas adsorption, X-ray powder diffraction, microcalorimetry and differential scanning calorimetry (DSC). We have found that BET gas adsorption and microcalorimetry being the best methods for distinguishing the different forms of the tested compounds.

Test Results

0028The surface area measured by determining the quantity of a gas (nitrogen) that adsorbs as a single layer of molecules, a monomolecular layer on a sample is formed (Flowsorb II 2300, Micromeritics Co., USA). Surface area after the sample has. been standing in high humidity for 24 hours. <tables id="tabl0001" num="0001"><table frame="all"><tgroup cols="3" colsep="1" rowsep="1"><colspec colnum="1" colname="col1" colwidth="52.50mm" /><colspec colnum="2" colname="col2" colwidth="52.50mm" /><colspec colnum="3" colname="col3" colwidth="52.50mm" /><thead valign="top"><row><entry namest="col1" nameend="col1" align="left">Micronised substance (m²/g)</entry><entry namest="col2" nameend="col2" align="left">Non-conditioned substance (m²/g)</entry><entry namest="col3" nameend="col3" align="left">Conditioned substance (m²/g)</entry></row><row><entry namest="col1" nameend="col3" align="left">Terbutaline sulphate:</entry></row></thead><tbody valign="top"><row><entry namest="col1" nameend="col1" align="left">11-12.5</entry><entry namest="col2" nameend="col2" align="left">&lt;3</entry><entry namest="col3" nameend="col3" align="left">7 - 9</entry></row></tbody></tgroup><tgroup cols="3" colsep="1" rowsep="1"><colspec colnum="1" colname="col1" colwidth="52.50mm" /><colspec colnum="2" colname="col2" colwidth="52.50mm" /><colspec colnum="3" colname="col3" colwidth="52.50mm" /><thead valign="top"><row><entry namest="col1" nameend="col3" align="left">Salbutamol sulphate:</entry></row></thead><tbody valign="top"><row rowsep="1"><entry namest="col1" nameend="col1" align="left">8.4</entry><entry namest="col2" nameend="col2" align="left">3</entry><entry namest="col3" nameend="col3" align="left">5.9</entry></row></tbody></tgroup></table></tables>

0029With low surface area, obtained when micronised substance has been stored at high humidity, the bulk substance has a great tendency to aggregate when stored, which makes the substance very difficult for technical handling in manufacturing the different formulations needed.

0030The interactions between certain substances and water vapour have also been studied by microcalorimetry. When said substances are subjected to water in the vapour phase they give off heat in a highly co-operative process. This moisture induced phase transition is however not observed for the conditioned substance. Thus, the conditioning process transforms the substance into a more stable form that is less sensitive to humidity.

0031Comparison of the heat given off by non-conditioned and conditioned substances when subjected to water vapour. Experiments are performed by a Thermal Activity Monitor 2277 (Thermometrics, Sweden). <tables id="tabl0002" num="0002"><table frame="all"><tgroup cols="3" colsep="1" rowsep="1"><colspec colnum="1" colname="col1" colwidth="52.50mm" /><colspec colnum="2" colname="col2" colwidth="52.50mm" /><colspec colnum="3" colname="col3" colwidth="52.50mm" /><thead valign="top"><row><entry namest="col1" nameend="col1" /><entry namest="col2" nameend="col2" align="left">Heat (J/g)</entry><entry namest="col3" nameend="col3" /></row><row><entry namest="col1" nameend="col1" align="left">Relative humidity (%)</entry><entry namest="col2" nameend="col2" rowsep="0" align="left">Non-conditioned substance</entry><entry namest="col3" nameend="col3" rowsep="0" align="left">Conditioned substance</entry></row><row><entry namest="col1" nameend="col1" align="left">Terbutaline sulphate</entry><entry namest="col2" nameend="col2" /><entry namest="col3" nameend="col3" /></row></thead><tbody valign="top"><row rowsep="0"><entry namest="col1" nameend="col1" align="left">58</entry><entry namest="col2" nameend="col2" align="left">3.6</entry><entry namest="col3" nameend="col3" align="left">0.1</entry></row><row><entry namest="col1" nameend="col1" align="left">75</entry><entry namest="col2" nameend="col2" align="left">6.2</entry><entry namest="col3" nameend="col3" align="left">0.1</entry></row></tbody></tgroup><tgroup cols="3" colsep="1" rowsep="1"><colspec colnum="1" colname="col1" colwidth="52.50mm" /><colspec colnum="2" colname="col2" colwidth="52.50mm" /><colspec colnum="3" colname="col3" colwidth="52.50mm" /><thead valign="top"><row><entry namest="col1" nameend="col1" align="left">Salbutamol sulphate</entry><entry namest="col2" nameend="col2" /><entry namest="col3" nameend="col3" /></row></thead><tbody valign="top"><row rowsep="1"><entry namest="col1" nameend="col1" align="left">75</entry><entry namest="col2" nameend="col2" align="left">6-8</entry><entry namest="col3" nameend="col3" align="left">0.1</entry></row></tbody></tgroup></table></tables>

0032The stability of the particles being conditioned were astonishing and will in a remarkable way increase the flexibility of the use of the substance for different formulations.

Experimental procedure

0033The invention is further illustrated but not limited by the following example.

Example 1

00343.6 kg terbutaline sulphate micronised was dried in a stainless steel column with 200 mm diameter at 90°C in vacuum for 23 hours. The dried substance was cooled to about 30°C and the pressure was normalised with ethanol-saturated nitrogen gas. 70 ml/min of ethanol-saturated nitrogen gas was then passed through the 200 mm diameter column for 60 hours to condition the substance. During this time the column was inverted a few times. The residual solvent was eliminated by purging with nitrogen gas for 2 hours and the product, about 3.5 kg. was packed in double plastic bags with a drying agent between the bags.

Example 2

0035In one experiment 1 g micronised salbutamol sulphate was kept at room temperature for 24 hours in a closed vessel containing a beaker filled with ethanol. The sample was removed and stored in a completely dry environment over night in order to eliminate traces of ethanol. The sample was subjected for analysis (see test results given above).

0036It is necessary to introduce stirring or tumbling of the substance when conditioning in larger scale.