WO2008087401A1 - Sulfate salts of irbesartan and their preparation and pharmaceutical compositions - Google Patents

Abstract

The present invention relates to novel sulfate salts of irbesartan and to their use in medical therapy, in particular to their use in the treatment and/or prophylaxis of disorders associated with hypertension, chronic renal failure, and diabetic neuropathy.

Description

SULFATE SALTS OF IRBESARTAN AND THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS

The present invention relates to novel salts of irbesartan and to their use in medical therapy, in particular to their use in the treatment and/or prophylaxis of disorders associated with hypertension, chronic renal failure, and diabetic neuropathy.

The present invention also relates to processes for preparing these novel salts of irbesartan.

Irbesartan i.e. 2-butyl-3-[p-(o-lH-tetrazol-5-ylphenyl)benzyl]-l,3-diazaspiro[4,4]non-l-en-4- one otherwise, 2-butyl-3-[[2!-(lH-tetrazol-5-yl)[l,l'-biphenyl]-4-yl]methyl]-l,3- diazaspiro[4,4]non- 1 -ene-4-one, otherwise 2-n-butyl-4-spirocyclopentane- 1 -[(2'-(tetrazol-5- yl)biphenyl-4-yl)methyl]- 2-imidazolin-5-one may be prepared by the methods described in U.S. patent 5,270,317. Example 5 describes a procedure for the preparation of irbesartan in unsalted form as a white crystalline solid melting at 180- 181⁰C. The same example describes the preparation of a potassium salt monohydrate melting at 142-144°C. European Patent Application 708103 discloses the existence and methods for the preparation of 2 crystalline forms of unsalted irbesartan, designated form A and form B. European Patent Application 708103 indicates that form A irbesartan comprises stable, non-hygroscopic needles of high electrostatic nature. The preparation of an amorphous form of irbesartan is described in PCT WO 2003 50110. Further references to the preparation of irbesartan may be found in PCT WO 1991 14679, WO 2004 87136, WO 2004 65383, WO 2004 7482, and the Journal of Medicinal Chemistry Vol. 36 pp. 3371-3380, 1993. The following patents describe various uses, compositions, formulations, and combinations containing irbesartan, US Patents 5,270,317, 6,342,247, 6,800,761, 6,248,729, 5,994,348. All these patent applications and publications are incorporated herein in their entirety by reference. In particular, all information concerned with preparing the irbesartan active moiety from readily available starting materials is incorporated in full. In addition, it should be appreciated that all information concerning the incorporation of irbesartan into a formulation is herein incorporated by reference as is information on the use of such formulations in medical therapy.

Irbesartan is one of many compounds described in US patent 5,270,317 and it is stated that these compounds are useful in the treatment of cardiovascular complaints such as hypertension and heart failure, as well as in the treatment of complaints of the central nervous system and in the treatment of glaucoma, diabetic retinopathy and renal insufficiency.

The fact that irbesartan is only available commercially as the crystalline unsalted neutral compound in numerous countries including the USA and EU would lead the skilled worker reviewing the art to believe that this is the preferred form of irbesartan. This fact would lead a skilled worker to believe that there is technical prejudice in the prior art against the use of salts. The compounds of the present invention are not prima facie obvious over the disclosures in the art.

Irbesartan is the active ingredient in Aprovel® and Avapro® and one of the active ingredients in Coaprovel® which have been approved for use in the treatment of hypertension and diabetic neuropathy with an elevated serum creatinine and proteinuria. The choice of a form of a pharmaceutical agent having an acidic functional group is not a matter of routine. The fact that Sanofi/BMS (the originator companies) only market the unsalted compound could lead one skilled in the art to believe that other forms were less preferred. The choice of salts arid forms of irbesartan other than the prior art forms is not therefore prima facie obvious in view of this technical prejudice and other concerns about the formation and properties of such salts and forms. There are problems and technical hurdles to be overcome when selecting a salt or form other than the crystalline unsalted compound and crystalline potassium salt such as whether a different salt or form can exist at all, whether the properties of such a salt or form would be satisfactory, comparable or better than the prior art forms. Whether a suitable method exists for the preparation of a salt or form other than the prior art forms is not a matter of routine experimentation.

There is a need to find alternative forms of irbesartan other than the prior art forms which are pharmaceutically acceptable, and which have improved stability, purity or ease of use compared to the prior art forms, especially the known amorphous forms. Such forms apart from finding use in medical therapy and as intermediates are also useful in providing new active ingredients containing the active moiety irbesartan which could form the basis for providing new value-added line extension products in the form of advantageous formulations or new uses. We have surprisingly found that useful novel irbesartan sulfate salts can be prepared.

In the above-mentioned publications there are no descriptions let alone any enabling disclosures of any irbesartan sulfate salts, and no disclosures of pharmaceutically acceptable solutions or dispersions in carriers.

Unexpected advantages for the compounds of the present invention may also be present. Such potential advantages are listed below:

An important property of a drug substance is its solubility in water and in other solvents. There is a link between solubility and bioavailability in as much as very water-insoluble drugs can only be made bioavailable by very careful formulation. The need for high solubility in water or other parenteral media is self-evident, and in general both high, moderate, or low solubilities can be important for different formulations. Formulations designed for sustained release may benefit from very low aqueous solubility. Apparatus and procedures for the measurement of solubility are described in detail in both the European Pharmacopoeia 4^th edition 2001, and United States Pharmacopeia 24^rd edition 1999-2003. The irbesartan sulfate salts of this invention have appreciably higher aqueous solubility than the prior art crystalline unsalted compound. The aqueous solubility of the crystalline irbesartan sulfate of example 2 is greater than 2% weight/weight at 11⁰C. At elevated temperatures the aqueous solubility is higher, for example greater than 5% weight/weight at 100°C.

Another property that influences the ability of a drug substance to go into solution and which varies among different solid forms of a drug substance is the degree of wetting, which affects the rate of dissolution. Wetting is the ability of liquids to form boundary surfaces with solid materials, and is determined by measuring the contact angle which a liquid forms in contact with a solid. The smaller the contact angle the larger the wetting tendency. Wetting phenomena are described in Remington: The Science and Practice of Pharmacy 20th edition, Alfonso R Gennaro editor, Lippincott, Williams, and Wilkins, Philadelphia USA on pages 278-9. In order for immersion of a solid to occur, the liquid must displace air and spread over the surface of the solid. When liquids cannot spread over a solid surface spontaneously, and therefore the spreading coefficient S is negative, it is said that the solid is not wetted. An important parameter reflecting the degree of wetting is the angle made by the liquid with the solid surface at the point of contact By convention, when wetting is complete, the contact angle is 0°. In non-wetting situations it theoretically can increase to a value of 180°, where a spherical droplet makes contact with solid at only one point.

There may be advantages during manufacture in terms of the timing and cost of production, reproducibility, and safety.

There may be advantages during manufacture in terms of improved yield and purity. The yield is established by comparison of the weights of cost-critical starting materials and product making allowance for molecular weights and purities. Purities are established by hplc, gc or other conventional analytical methods by means of validated procedures and comparison with reference standards. See for example Remington: The Science and Practice of Pharmacy 20th edition, Alfonso R Gennaro editor, Lippincott, Williams, and Wilkins, Philadelphia USA, ISBN 0-683-306472, page 597.

There may be advantages during manufacture in terms of improved filterability, for example the avoidance of clogging or blinding of filter cloths, and the need for large or expensive or sophisticated filtration apparatus. Filterability testing procedures are based on the concept of V_max. V_max modelling is based on the theory that there is some maximum volume of a fluid which will pass a filter at a given pressure. At that point, the flow across the filter will be zero and therefore infinite resistance of the pad to flow . On the basis of this model the rate of flow of filtrate is proportional to the driving force and the cross-sectional area of the filter bed. Measurements of flow rates and timing of standardised operations may be used to demonstrate advantage.

There may be advantages during manufacture in terms of improved washability which result from the physical properties of the material and the size, shape and surface properties of any particles which are present, which physical properties are not per se predictable. Quantification is possible by measurement of, for example, the volume and cost of solvent, duration of agitation, and number of washes required to achieve a standardised reduction in adherent impurity levels. Another relevant factor which would constitute an advantage is a reduction in the loss of product resulting from washing procedures. There may be advantages during manufacture in terms of improved ease of drying which also result from the physical properties of the material and the size, shape and surface properties of the material, which are not per se predictable. Quantification is achievable by measurement of the length of time and temperature in a specific drying apparatus to achieve a standardised reduction in the solvent level in a standardised quantity of product. Other relevant factors which may give rise to an advantage include the need for agitation, and the need for or suitability for use in efficient apparatus such as filter driers.

Improvements in the colour of a product are linked in perception and often in reality with purity and quality, so may constitute a valuable advantage. Standard colour tests are described in the major pharmacopoeias, for example the European Pharmacopoeia 4^th edition 2001 , and United States Pharmacopeia 24^Td edition 1999-2003 and for example USP 2000 page 1926. Colour may be defined as the perception or subjective response of an observer to the objective stimulus of radiant energy in the visible spectrum extending over a range 400 run to 700 nm in wavelength. Three attributes are commonly used to identify a colour: 1) hue, or the quality by which one colour family is distinguished from another, such as red, yellow, blue, green and intermediate terms; 2) value, or the quality that distinguishes a light colour from a dark one; and 3) chroma, or the quality that distinguishes a strong colour from a weak one, or the extent to which a colour differs from a grey of the same value. The perception of colour and colour matches is dependent on conditions of viewing and illumination. Determinations should be made using diffuse, uniform illumination under conditions that reduce shadows and nonspectral reflectance to a minimum. The surfaces of powders should be smoothed under gentle pressure so that a planar surface free from irregularities is presented. Liquids should be compared in matched colour-comparison tubes, against a white background. If results are found to vary with illumination, those obtained in natural or artificial daylight are to be considered correct. Colours of standards should be as close as possible to those of the test specimens for quantifying colour differences. Instrumental methods for measurement of colour provide more objective data than the subjective viewing of colours by a small number of individuals.

The extent to which a product is associated with chemical impurities arising from earlier stages of synthesis is essentially unpredictable and depends both on the synthetic process, the nature of reagents used in the process, and on the physical, chemical, and surface properties of the product. For example a novel salt, polymorph, or pseudopolymorph will have a different and unpredictable profile of trace impurities than a comparator salt. The crystalline irbesartan sulfate salt of this invention forms good crystals and is of value in the purification of irbesartan products. Once formed, the sulfate can be converted to unsalted irbesartan of high purity by neutralisation in either aqueous or alcoholic or mixed solvents. Quantification of purity may be achieved by measurement and characterisation of impurity profiles, for example by GC-MS or LC-MS analysis and comparison with a reference material. Identification of all impurities is not essential providing sufficient characterisation is obtained from the analytical methodology, though it is of course desirable.

From the point of view of manufacturing and formulation efficiency high bulk density in a product is generally regarded as an advantage, since it allows for smaller apparatus and more acceptable unit doses. Furthermore, the need for costly grinding and compaction procedures can be avoided or at least reduced. The European Pharmacopoeia describes definitions and methods by which bulk density of a powder may be measured. Apart from the inherent density of a material which depends on factors such as crystal structure which is unpredictable, there is also the contribution of interparticulate void volume which is equally unpredictable. The bulk density is determined by measuring the volume of a known mass of powder, which has been passed through a screen, into a graduated cylinder. The tapped density is achieved by mechanically tapping a measuring cylinder containing a powder sample. After observing the initial volume, the cylinder is mechanically tapped, and volume readings are taken until little further volume change is observed. The crystalline irbesartan sulfate of the examples of this invention has higher bulk density than the crystalline unsalted irbesartan which forms the active ingredient of Aprovel® and Avapro® .

The ability of a powder to flow efficiently through manufacturing apparatus is a significant factor affecting the economics of manufacture and will vary according to the form of material. For example different salts, polymorphs, and pseudopolymorphs will have different inherent flow properties, though isolation procedures will also have an effect. Suitable definitions and methods of measurement are described in standard reference texts, for example European Pharmacopoeia 4^th edition 2001, and United States Pharmacopeia 24^rd edition 1999-2003 and Remington: The Science and Practice of Pharmacy 20th edition, Alfonso R Gennaro editor, Lippincott, Williams, and Wilkins, Philadelphia USA. Measurement may be for example in terms of the angle of repose, which may be determined experimentally by a number of methods with slightly differing results. A typical method is to pour the powder in a conical heap on a level, flat surface and measure the included angle with the horizontal. The crystalline irbesartan sulfate of the examples of this invention flows more freely than the crystalline unsalted irbesartan which forms the active ingredient of Aprovel® and Avapro®.

One of the factors affecting the safety of a manufacturing process and hence the cost of the manufacturing facility is the flammability of a material. Typical measurement procedures include the "Burning Rate Test" or "Fire Train Test" as defined in United States Department of Transportation and United Nations regulations (49 CFR 173 Appendix E and UN Recommendations on the Transport of Dangerous Goods, also EEC Directive 79/831 Annex Part A: Methods for the Determination of Physico-Chemical Properties 3.10 Flammability of Solids. A typical test involves applying a source of ignition to a powder "train" measuring 250 mm x 20 mm x 10 mm and measuring the rate at which the powder burns.

Another unpredictable property of particulate pharmaceutical products which affects safety and hence cost of manufacture is the tendency to produce dusts or fines during processing, which dusts or fines vary in their hazardous nature. This property is associated with the static electrical properties of the material. Standard test methods and protocols exist to quantify these problems. For example BS 5958 part 1 - Code of practice for control of undesirable static electricity, British Standards Institute, 1991; VDI Fortschritt-Berichte 2263; ISO 6184/1 ; IEC 1241-2-1, Electrical apparatus for use in the presence of combustible dust Part 2: Test methods, Section 1 : Methods for determining the minimum ignition temperatures of dust. International Electrotechnical Commission, first edition, 1994-12. European Patent Application 708103 indicates that unsalted irbesartan is highly electrostatic, whereas the crystalline irbesartan sulfate of the examples of this invention was not observed to be significantly electrostatic.

Alternative forms of a drug substance may have unpredictably different chemical stabilities and so produce a quantifiable advantage for one form over the other. Standard test methods are described in the major pharmacopoeias and are also referenced on the US Food and Drug Administation Web site. Typically, accelerated storage tests are performed by storage for a period of 1 year or more at elevated temperature (e.g. 4O⁰C) and at standard humidity conditions (e.g. 75% RH), with samples being taken at regular intervals of approximately 1 month and assayed for overall purity, specific impurities, and a general impurity screen.

In addition, chemical interactions between drug substance and typical excipients used for formulation will differ for different forms of a drug substance, making one form advantageous in one formulation, though not necessarily advantageous in a different formulation. Examples of chemical interactions between drug substance and excipients include the interaction between amine drugs and lactose.

Stability to irradiation, especially visible and ultra-violet light is of increasing importance in pharmaceutical science and represents another area in which alternative forms of a drug substance may have significantly and unpredictably different properties. Testing details, such as light source, flux density, and duration are described in Federal Register Notices Volume 62, Number 95, pages 27115-27122, together with recommendations for analytical methodology and assessment of results.

Pharmaceutical materials with relatively high melting points are generally easier to formulate and are subject to less attrition and clumping during processing. Melting points and glass transition temperatures will differ greatly for different salts, polymorphs, pseudopolymorphs, or other forms of a drug and are in essence unpredictable. Methods for measuring melting points are well-described in the European Pharmacopoeia 4^th edition 2001, and United States Pharmacopeia 24^rd edition 1999-2003. Various methods are acceptable but differ in detail, for example the melting point determined by the capillary method is the temperature at which the last solid particle of a compact column of a substance in a tube passes into the liquid phase. Suitable apparatus is described in the above mentioned publications and may be calibrated using melting point reference substances such as those of the World Health Organisation or other appropriate substances.

Some materials have a tendency to change their physical form during storage, which can be a disadvantage in pharmaceutical manufacture. For example materials can settle and compact and lose their ability to flow freely. One polymorphic form may wholly or partially convert to another over an uncertain time-frame, or solvates and hydrates may lose their solvent or water, and the resultant change in the physical properties of the drug substance can lead to a formulation with uncertain, unreliable, and unpredictable characteristics. Clearly a polymorphic conversion can only occur from a less stable to a more stable form, so there are advantages associated with thermodynamic stability, and the relative stability of a novel form is a priori unpredictable.

All substances absorb moisture when exposed to different relative humidity environments, but the extent and humidity response and temperature response varies very considerably.

The term hygroscopicity is used to describe both the rate and the extent of water uptake. It is well established that hygroscopic products are difficult to handle and hence more expensive to formulate. Hygroscopicity is not a priori predictable, and an alternative salt may well be advantageous in this respect. Apparatus for measurement of moisture contents of samples under controlled humidity conditions is available commercially, e.g from I Holland Ltd., Nottingham, U.K. Simple measurements may be made by monitoring the appearance and weight of samples exposed to atmospheres of known constant humidity and temperature, as described in, for example, The Merck Index 12^th edition, Merck and Co Inc. The crystalline irbesartan sulfate of the examples of this invention has very low hygroscopicity.

The ability of different forms of a drug to admix with specific common excipients across the formulation / delivery range of technologies is very important and will differ in a non- predictable manner depending on the specific properties of the drug form. Pharmaceutical excipients are substances, other than the active pharmaceutical ingredient, that are used in the ^' finished dosage form. There are very many widely differing excipients each with particular characteristics which form the basis of many widely differing formulations. Excipients and their properties are described in detail in the pharmaceutical literature, for example in Remington: The Science and Practice of Pharmacy 20th edition, Alfonso R Gennaro editor, Lippincott, Williams, and Wilkins, Philadelphia USA. They serve many functions, for example they stabilise the drug substance by providing antioxidant, heavy-metal chelating, or light-protection properties. They also may be used to enhance bioavailability and to control the release of drug substance from dosage forms. For solid dosage forms, they provide suitable characteristics for dispensing the drug substance in accurate dosage units that have reproducible release properties. Diluents provide a flowable bulk, binders hold powders together after wet granulation, lubricants provide punch-releasing properties, and disintegrants help to disperse dosage forms in the gastrointestinal tract. There is a risk, which may be avoided by careful selection of the form of the drug, of incompatibilities between drug substance and excipients. Screens to detect drug-excipient incompatibilities have been developed using elevated temperature and added water to accelerate potential interactions in ternary and more complex powder blends (Serajuddin ATM ef α/Pharm Res 1991 8(suppl): S 103) and such methods have been shown to be capable of rapidly detecting chemical incompatibilities.

The present invention provides novel amorphous and crystalline and liquid irbesartan sulfate. Different stoichiometries are possible and irbesartan sulfate salts may be produced with a stoichiometry of one molecule of irbesartan to one molecule of sulfuric acid or with a stoichiometry of two molecules of irbesartan to one molecule of sulfuric acid or mixtures of the two forms with intermediate stoichiometry. All these stoichiometries of irbesartan sulfate salt are included within the scope of this invention.

In the first aspect of this invention the novel forms of irbesartan sulfate are crystalline forms. A preferred crystalline form is the colourless, crystalline salt described below in the examples. However, more than one novel crystalline form may be possible and such polymorphs and pseudopolymorphs including hydrates and solvates also form an aspect of this invention.

Alternatively, irbesartan sulfate may be in the form of amorphous oils, gums or solids. Such amorphous irbesartan sulfate may be used as an ingredient for inclusion in a range of formulations such as conventional tablets and capsules, or may be prepared in a form in which the salt is absorbed in a carrier, for example an excipient or a mixture of excipients for tabletting or other formulation, or as a solution in a wax or similar pharmaceutically acceptable polymer, such as PEG or PVA.

Alternatively, the novel irbesartan sulfate may be in liquid form. Such liquids may be prepared by conventional methods such as dissolving a crystalline or amorphous material in a suitable solvent. If aqueous solutions are prepared a small amount of sulfuric acid may be added to the aqueous medium to prevent disproportionation.

Examples of novel irbesartan sulfate include: Amorphous irbesartan sulfate Crystalline irbesartan sulfate Solutions of irbesartan sulfate Solid dispersions of irbesartan sulfate Irbesartan sulfate absorbed onto carriers Mixtures of the above forms

Examples of carriers which are suitable for use with the salts of this invention and which are capable of supporting a high salt loading are magnesium aluminometasilicate e.g. Neusilin® US2 and N-Zorbit® food grade starch. It will be appreciated that other carriers may also be used with the irbesartan sulfate salts of this invention and their capacity and the stability of the resulting product may be determined by routine experiment. Examples of other carriers include, but are not limited to starch, microcrystalline cellulose, sodium carboxymethylcellulose, trehalose, laevulose, lactilol, xylitol, maltodextrin, sorbitol, methyl cellulose, ethyl cellulose, hydroxypropylcellulose, pregelatinised starch, calcium hydrogenphosphate, maltose, lactose, cellulose, talc, Amberlite ® XAD-4, Amberlite ® XAD-7, Amberlite ® XAD-16, AMBERSORB ® 348F, AMBERSORB ® 563, AMBERSORB ® 572, Activated carbon, Activated carbon Darco ®, Activated carbon Darco ® G-60, Activated carbon Darco ® KB, Activated carbon Darco ® KB-B Activated carbon Norit ®, silica gel high purity grades with high pore volume e.g. 0.75 cc/g, and average pore diameter 6θA.

It will be appreciated that mixtures of more than one carrier may be used.

The preparation of unsalted irbesartan is described in U.S. patent 5,270,317. Example 5 describes a procedure for the preparation of irbesartan as a white crystalline solid melting at 180-181⁰C. The same example describes the preparation of a potassium salt monohydrate melting at 142-144°C. The preparation of an amorphous form of irbesartan is described in PCT WO 2003 50110. All these patent specifications are incorporated herein by reference. Sulfuric acid is available commercially. These compounds may be used as source materials for the preparation of the irbesartan sulfate salts of this invention.

Solutions of the sulfate salts of this invention may be prepared by contacting a suitable source of irbesartan with a suitable source of sulfuric acid. Most conveniently irbesartan is in unsalted form and the sulfuric acid is in the form of an aqueous solution. The irbesartan source may initially be in solid form or in solution, which solution may be either an aqueous solution or a solution in an organic solvent or a solution in a mixed aqueous/organic solvent. In addition to unsalted irbesartan, other salts of irbesartan may be used, such as for example the prior art potassium salt or other salts with organic or inorganic bases. In addition the irbesartan may be generated in situ from a chemical precursor. Suitable solutions of irbesartan have been described in above-quoted references. For example irbesartan itself may be dissolved in hot absolute ethanol at a concentration of 1 gramme in 10 ml, or in propan-2- ol at a concentration of 1 gramme in 20 ml, or in a mixture of water and ethanol (1 :3 by volume) at a concentration of 1 gramme in 11 ml, or with greater solubility in pure ethanol or ethanol containing a smaller proportion of water at greater concentration, with ultrasonication and heating. Alternatively irbesartan may be dissolved in a mixture of propan-2-ol and methanol (1 :1 by volume) at a concentration of 1 gramme in 40 ml at ambient temperature, or at greater concentration at elevated temperature. Crystalline and non-crystalline irbesartan will also dissolve in sulfuric acid solutions such as aqueous, or mixed aqueous alcoholic solutions.

Solutions of irbesartan sulfate may also be prepared from crystalline or non-crystalline irbesartan sulfate by dissolving in a suitable solvent, for example in an aqueous, alcoholic or mixed aqueous alcoholic solvent. A particularly preferred solvent is ethanol. If aqueous solutions are prepared a small amount of sulfuric acid may be added to the aqueous medium to prevent disproportionation.

Suitable solution concentrations of reagents for the preparation of the irbesartan sulfate salts of this invention are between 0.5% to 20% by weight. Reactions of solids with solutions are allowed to proceed until substantially all the solid has reacted, which may require between 10 minutes and 10 hours or longer, but the time required may be shortened by use of elevated temperatures and ultrasonication. At least a stoichiometric quantity of sulfuric acid is advantageously used, but an excess, for example between 2 and 20 molecular equivalents, is preferred. ^l

The irbesartan sulfate solution may be combined at this stage with excipients, absorbants, carriers or dispersion matrix media, either as solids or in solution.

Amorphous forms of irbesartan sulfate may then be isolated by either vacuum evaporation, spray-drying, precipitation with an anti-solvent, or freeze drying, however the aqueous solubility of irbesartan sulfate is not high enough to make freeze-drying a preferred method for routine isolation.

If a vacuum evaporation technique is used to isolate amorphous forms of irbesartan sulfate, it should be carried out as rapidly as possible and under conditions which avoid the presence of seeds of the crystalline salt so as to minimise crystallisation of the salt. Alcoholic or mixed aqueous/alcoholic solvents are preferred to 100% aqueous solvent, and ethanol is particularly advantageous.

If a spray-drying technique is used, a concentration of between 1% and 40% weight/volume may be used, comprising irbesartan sulfate in solution and any excipients and/or dispersion media and/or carriers in finely powdered form or in solution, optionally at elevated temperature, though a concentration of between 10 and 40% is preferred. Stock mixtures containing organic solvents may be spray dried in a closed loop spray dryer. The apparatus parameters are adjusted to give an acceptable product by routine means, but control of outlet gas temperature and solvent content of the outlet gas is particularly important. Hence it is preferred that the outlet temperature is kept above 3O⁰C but below 7O⁰C, more preferably below 5O⁰C, and the solvent content of the outlet gases is kept below 2 grammes per 100 grammes, more preferably below 1.2 grammes per 100 grammes. If a solid carrier or absorbant is used, outlet temperatures above 5O⁰C may be acceptable so long as the solid carrier or absorbant retains a free-flowing character at such temperatures. The technology of spray drying is described in the following publications which are incorporated herein by reference: Spray-drying handbook 5th edition by K Masters, Longman Scientific & Technical, 1991 ISBN 0582062667; Spray-drying of pharmaceuticals for controlled release pulmonary drug delivery by Noha Patel, University of Bath, 2000; Spray-drying of particles intended for inhalation by Kristina Mos'em, Department of Pharmaceutics, Copenhagen, Danish University of Pharmaceutical Sciences 2003, ISBN 8778345243. Known techniques may be employed to coat the particles with enteric or other known coatings for control of drug release after administration.

Drying to the full extent that is desirable for a stable pharmaceutical product is not always practicable during efficient use of the isolation apparatus, particularly in the case of spray- drying, so in all the above procedures a final air or vacuum drying step may be necessary to reduce residual water and solvent to an acceptable level.

Crystalline irbesartan sulfate may be prepared by following the same procedures as have been described for the preparation of irbesartan sulfate solutions and then seeding with crystalline irbesartan sulfate, concentrating, cooling, or adding an anti-solvent and then allowing sufficient time for crystallisation to take place. Alternatively crystalline irbesartan sulfate may be prepared by seeding and/or triturating the amorphous salt with a solvent such as water, acetone, or an alcohol such as ethanol or propan-2-ol, or mixtures. Other solvents may also be used as determined by routine experimentation. A preferred method of preparing crystalline irbesartan sulfate is to add sufficient aqueous sulfuric acid, for example between 1 and 5 molar, to a vigorously stirred slurry of unsalted irbesartan in water, preferably at elevated temperature, for example at reflux, until a clear solution is obtained. Cooling and evaporating the solution results in the formation of a gum which crystallises on seeding. Seeding during the evaporation process results in the formation of crystalline irbesartan sulfate without appreciable gum formation.

The irbesartan sulfate of this invention also has the potential to be prepared as solid or liquid solutions or dispersions in a liquid or polymeric carrier or matrix.

Such matrix dispersions may be prepared in a variety of ways; the irbesartan sulfate may be added to the matrix material either as a solid or in solution, and the matrix material itself may also be either in the form of a solid (or liquid, as appropriate) or in solution. If both materials are solids then heating and stirring of a melt may be utilised to form a homogenous mixture before the product is cooled, and either ground to a powder, or left as a liquid or semi-liquid suitable for further formulation. Various techniques are known for the formation of suitable granules and platform products from melts, for example spray congealing techniques to produce pellets have been described by Kanig J.Pharm Sci 53, 188, 1964 and by Kreuschner et al. Acta Pharm. Tech. 23, 159, 1980. A liquid matrix may be used to dissolve the solid irbesartan sulfate, or a solution of the matrix product may be formed by mixing a solution of the irbesartan sulfate with a solution of the matrix material, and the solvent subsequently removed by evaporation or spray-drying. Suitable solvents for preparing solid or liquid solutions or dispersions include water, common alcohols, ketones, esters, and ethers. Preferred solvents are those in which the matrix materials are soluble including water, methanol, ethanol, propan-2-ol, and mixtures thereof.

In a variation on the procedures described above for the preparation of amorphous irbesartan sulfate, the liquid or polymeric carrier or matrix material or solution thereof may form the solvent for the salt formation reaction. Hence the irbesartan and sulfuric acid components may be added separately to the matrix material or solution thereof, optionally with heating to produce a melt or otherwise ensure a homogenous mixture. The product may then be cooled or evaporated and further treated to produce a form suitable for further formulation.

Suitable ratios of irbesartan sulfate to liquid or polymeric carrier or matrix material may vary from 1 : 100 to 10: 1 , preferably from 1 :20 to 3 : 1.

If a volatile solvent is used to form the matrix dispersion, it may be difficult to remove it all by evaporation. In the case of solvents such as water or ethanol this is not a problem and substantial residues may be tolerated, indeed may improve the stability and properties of the product. However residues which decrease the viscosity to the extent that crystallisation may occur on storage are undesirable. Less desirable solvents must be removed sufficiently by extended, optionally elevated temperature evaporation to ensure a pharmaceutically acceptable product.

Suitable liquid or polymeric carrier or matrix materials include the following: animal, vegetable or mineral oils, fats, waxes, chocolate, chewing gum base, maize oil, lecithin, groundnut oil, sunflower oil, cottonseed oil, lauroylmonoglyceride, lanolin, gelatin, isinglass, agar, carnauba wax, beeswax, polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), _v polyethylene glycol esters, ovalbumin, soybean proteins, gum arabic, starch, modified starch, crospovidone, hydroxypropyl cellulose, methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, cellulose acetate phthalate, cellulose acetate butyrate, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, ethyl cellulose, chicle, polypropylene, dextrans, including dexran 40, dextran 70 and dextran 75, dextrins, alpha-, beta-, gamma-cyclodextrins, hydroxypropyl-beta-cyclodextrins, alkylpolyglucosides, chitosan, polyvinylacetate, ethylene vinyl acetate, lectins, carbopols, silicon elastomers, polyacrylic polymers, maltodextrins, lactose, fructose, inositol, trehalose, maltose, rafflnose, lauryl alcohol, polysorbate 80, almond oil; babassu oil; borage oil; blackcurrant seed oil; canola oil; castor oil; coconut oil; corn oil; cottonseed oil; evening primrose oil; grapeseed oil; groundnut oil; mustard seed oil; olive oil; palm oil; palm kernel oil; peanut oil; rapeseed oil; safflower oil; sesame oil; shark liver oil; soybean oil; sunflower oil; hydrogenated castor oil; hydrogenated coconut oil; hydrogenated palm oil; hydrogenated soybean oil; hydrogenated vegetable oil; hydrogenated cottonseed and castor oil; partially hydrogenated soybean oil; soy oil; glyceryl tricaproate; glyceryl tricaprylate; glyceryl tricaprate; glyceryl triundecanoate; glyceryl trilaurate; glyceryl trioleate; glyceryl trilinoleate; glyceryl trilinolenate; glyceryl tricaprylate/caprate; glyceryl tricaprylate/caprate/laurate; glyceryl tricaprylate/caprate/linoleate; glyceryl tricaprylate/caprate/stearate; saturated polyglycolized glycerides; linoleic glycerides; caprylic/capric glycerides; modified triglycerides; fractionated triglycerides; and mixtures thereof.

Preferred materials are PVP and PEG, which are available in various grades differing chiefly in their mean molecular weight. In the case of PVP this may be between 2,000 and 3,000,000, however material in the range 8,000 to 500,000 is more preferred e.g. PVP K-15, K-30, K-40, K-90. In the case of PEG products the mean molecular weight may be in the range 200 to 20,000, but 1 ,000 to 10,000 is more preferred e.g. PEG 2000, PEG 8000.

It should be appreciated that the irbesartan sulfate salts of the present invention may be prepared on any suitable scale according to the procedures herein outlined and those procedures which are conventional to one skilled in the art of pharmaceutical chemistry, in particular in the preparation of salt forms. Techniques for scale-up are described in the literature_^fpr example Pharmaceutical Process Scale-Up by Michael Levin, Marcel Dekker, New York 2003, ISBN 0824706250, which publication is incorporated herein by reference. Once prepared as described above, amorphous and crystalline irbesartan sulfate, solid dispersions of irbesartan sulfate, irbesartan sulfate absorbed onto carriers, and liquid and solid solutions of irbesartan sulfate may be formulated into pharmaceutical compositions according to procedures well known in the art. Suitable procedures include those provided in

> Remington: The Science and Practice of Pharmacy 20th edition, Alfonso R Gennaro editor, Lippincott, Williams, and Wilkins, Philadelphia USA, ISBN 0-683-306472; The art, science, and technology of pharmaceutical compounding by Loyd V Allen, American Pharmaceutical Association, 2001, ISBN 1582120358 - incorporated herein by reference. Suitably, these compositions are adapted for oral use such as tablets, capsules, zydis, gums, candies, chocolates, sachet and oral liquids, or are adapted for topical use such as gels, lotions, patches, or ointments, or are adapted for parenteral use such as intravenous, intramuscular, or subcutaneous injection, or are adapted for use as suppositories, or are adapted for inhalation therapy such as bronchial or nasal inhalation therapy.

According to a further feature of the invention is a method of treating a disease or condition associated with hypertension, chronic renal failure, and diabetic neuropathy which comprises administering to a warm-blooded mammal an effective amount of the compounds of this invention. The invention also relates to the use of compounds of this invention in the manufacture of a medicament for use in a disease condition. According to a further feature of the invention there is provided a process for the manufacture of a pharmaceutical composition containing one or more of the compounds of this invention which comprises admixing one or more of the compounds of this invention with a pharmaceutically acceptable carrier. According to a further feature of the invention there is provided a pharmaceutical composition for use in the above-mentioned utilities which comprises a pharmaceutical composition containing one or more of the compounds of this invention.

Description of Figures

Figures 1 to 4 are representations of infra-red spectra measured by the nujol mull technique on a Perkin-Elmer Paragon 1000 infra-red spectrometer at 2 wavenumber resolution using 10 scans. Small quantities of the_sample material were mixed with nujol mineral oil to form a paste and pressed between sodium chloride windows. Background subtraction was performed to limit signals due to atmospheric water vapour and carbon dioxide. It will be appreciated that whilst every effort was made to ensure that the spectra were properly recorded, variation in individual technique, instrument, and apparatus may give rise to small differences when samples are analysed under different conditions. Varying residual signals due to atmospheric water and carbon dioxide and slight differences in peak intensities, position and resolution are normal in this analytical technique and the present invention is not limited to the exact details of the spectrum provided.

Figure 1 represents the nujol mull infra-red spectrum of the product of example 2 in the range 4000-450 wavenumbers.

Figure 2 represents the nujol mull infra-red spectrum of the product of example 2 in the range

2000-550 wavenumbers.

Figure 3 represents the nujol mull infra-red spectrum of the product of example 5 in the range

2000-550 wavenumbers. Figure 4 represents the nujol mull infra-red spectrum of the product of example 6 in the range

2000-550 wavenumbers.

The following examples are illustrative of the present invention and are not intended to limit it in any way:

Example 1

Preparation of crystalline irbesartan sulfate

Crystalline unsalted irbesartan (0.5 g) was slurried in water (20 ml) and heated to reflux. 2 molar aqueous sulfuric acid solution was added dropwise until an almost clear solution was obtained. A further quantity of water was added during the addition of acid to wash down deposits of irbesartan from the upper regions of the vessel (totalling approximately 10 ml). The resulting solution was filtered and slowly cooled. After standing overnight the clear solution was evaporated to a viscous gum, which was dissolved in a mixture of acetone and propan-2-ol. After standing for five days at about 5-10⁰C the gum was seen to have solidified. The solid was mobilised with tetrahydrofuran and the resulting crystalline solid was isolated by filtration and dried under vacuum. Yield 0.25 g of a white crystalline powder. A second crop of crystalline irbesartan sulfate was obtained by evaporation of the filtrate (0.26 g).

Example 2 Preparation of crystalline irbesartan sulfate

Crystalline unsalted irbesartan (0.6 g) was slurried in water (55 ml) and heated to reflux. 2 molar aqueous sulfuric acid solution was added dropwise (approximately 4 ml) until a clear solution was obtained. The solution was slowly cooled but remained clear, so it was evaporated to approximately 5 ml volume, during which time a quantity of gum separated from the solution. After seeding with the product of example land standing for about two hours, the product was found to be in the form of a crystalline solid. The product was isolated by filtration and dried under vacuum and phosphorus pentoxide overnight. Yield 0.53 g of white crystalline powder. The infra-red spectrum showed prominent absorption maxima at about 1769, 1635, 1509, 1067, 933, 754 and 666 wavenumbers.

Example 3

Preparation of non-crystalline irbesartan sulfate

Irbesartan sulfate from example 2 (0.1 g) was dissolved in absolute ethanol (10 ml) with warming and heated to reflux to destroy seeds of crystalline irbesartan sulfate. A clear solution was obtained and was evaporated under reduced pressure with the water bath set to

50⁰C to give a clear oil.

Example 4

Preparation of irbesartan sulfate in Neusilin® magnesium aluminometasilicate

The irbesartan sulfate from example 3 was dissolved in absolute ethanol (10 ml) to give a clear colourless solution. Neusilin® US2 magnesium aluminometasilicate (0.3 g) was added and the mixture stirred briefly and then left to stand for 1 hour. The slurry was then evaporated under reduced pressure with the water bath set to 50°C to produce a free-flowing white solid comprising irbesartan sulfate absorbed in Neusilin® US2 magnesium aluminometasilicate. After vacuum drying over phosphorus pentoxide the product was bottled. Weight 0.38 g.

Example 5 Preparation of crystalline irbesartan sulfate

Crystalline unsalted irbesartan (2.0 g) was slurried in water (50 ml) and heated to reflux. 2 molar aqueous sulfuric acid solution (approximately 6 ml) and a further 10 ml water was added dropwise until an almost clear solution was obtained. The solution was filtered and then slowly cooled. At first some gum formed but this quickly hardened. After standing overnight at ambient temperature a quantity of a crisp white solid was found to have formed. This solid was collected by filtration, washed with water, and briefly dried under vacuum to remove surface moisture. After air drying overnight a 1.85 g yield was obtained of a white crisp powder with a crystalline appearance. A further crop of white solid was also obtained. The infra-red spectrum of first crop material (see figure 3) exhibited absorption maxima inter αliα at about 1769, 1633, 1510, 1066, 933, and 755 cm^"1.

Example 6

Recrystallisation of irbesartan sulfate from propan-2-ol

Irbesartan sulfate from example 5 (1.0 g) was slurried in propan-2-ol (15 ml) and heated to reflux. A further volume of propan-2-ol was added until the total volume used was 60 ml.

The resulting refluxing clear solution was stirred and cooled slowly. On seeding with a small quantity of example 5 product, a white powdery precipitate formed. This product was filtered and dried under vacuum to give a yield of 0.71 g.

The infra-red spectrum (see figure 4) exhibited absorption maxima inter αliα at about 1762,

1644, 1505, 1039, 935, 851, and 755 cm^'1.

The residual liquors were evaporated to about 30 ml and a further crop of 0.1 Ig was obtained.

The utility of the compounds of this invention may be illustrated by standard tests and clinical studies.

Claims

1. Amorphous and crystalline and liquid irbesartan sulfate salts.

2. A sulfate salt according to Claim 1 wherein the novel form is an amorphous solid.

3. A sulfate salt according to Claim 1 wherein the novel form is a crystalline solid.

4. A sulfate salt according to Claim 1 wherein the novel form is a liquid.

5. A crystalline form of sulfate irbesartan according to Claim 3 wherein the novel crystalline form is a solvate or a hydrate.

6. An amorphous irbesartan sulfate salt with stoichiometry 2 irbesartan to 1 sulfate.

7. An amorphous irbesartan sulfate salt with stoichiometry 1 irbesartan to 1 sulfate.

8. A crystalline irbesartan sulfate salt with stoichiometry 2 irbesartan to 1 sulfate.

9. A crystalline irbesartan sulfate salt with stoichiometry 1 irbesartan to 1 sulfate.

10. A solution of irbesartan sulfate salt with stoichiometry 2 irbesartan to 1 sulfate.

11. A solution of irbesartan sulfate salt with stoichiometry 1 irbesartan to 1 sulfate.

12. A solid dispersion of irbesartan sulfate salt with stoichiometry 2 irbesartan to 1 sulfate.

13. A solid dispersion of irbesartan sulfate salt with stoichiometry 1 irbesartan to 1 sulfate.

^"14. An irbesartan sulfate salt with stoichiometry 2 irbesartan to 1 sulfate absorbed onto a carrier or carriers.

15. An irbesartan sulfate salt with stoichiometry 1 irbesartan to 1 sulfate absorbed onto a carrier or carriers.

16. An irbesartan sulfate salt according to claims 6 to 15 in which the stoichiometry is intermediate.

17. An irbesartan sulfate salt as prepared according to the procedures described in Example 1.

18. An irbesartan sulfate salt as prepared according to the procedures described in Example 2.

19. An irbesartan sulfate salt as prepared according to the procedures described in Example 3.

20. An irbesartan sulfate salt as prepared according to the procedures described in Example 4.

21. An irbesartan sulfate salt as prepared according to the procedures described in Example 5.

22. An irbesartan sulfate salt as prepared according to the procedures described in Example 6.

23. An irbesartan sulfate salt as described in claim 18 in which the infra-red spectrum is as represented by figure 1.

24. An irbesartan sulfate salt as described in claim 18 in which the infra-red spectrum shows absorption maxima at about 1769, 1635, 1509, 1067, 933, 754 and 666 wavenumbers.

25. An irbesartan sulfate salt as described in claim 21 in which the infra-red spectrum shows absorption maxima at about 1769, 1633, 1510, 1066, 933, and 755 wavenumbers.

26. An irbesartan sulfate salt as described in claim 22 in which the infra-red spectrum shows absorption maxima at about 1762, 1644, 1505, 1039, 935, 851, and 755 wavenumbers.

27. A method of treating a disease or condition associated with hypertension, chronic renal failure, or diabetic neuropathy which comprises administering to a warmblooded mammal an effective amount of the compounds of this invention.

28. The use of compounds of this invention in the manufacture of a medicament for use in a disease condition.

29. A process for the manufacture of a pharmaceutical composition containing one or more of the compounds of this invention which comprises admixing one or more of the compounds of this invention with a pharmaceutically acceptable carrier.

30. A pharmaceutical composition for use in medical therapy which comprises a pharmaceutical composition containing one or more of the compounds of this invention.