State of the art Disodium pamidronate is an amino-substituted biphosphonate of formula : This compound has been synthesised with the aim of mimicking the action of the pyrophosphates present in biological fluids, capable of inhibiting the precipitation of the calcium phosphates, obtaining at the same time an increased resistance to enzymatic hydrolysis (Fleisch H. and Neuman W. F, American Journal of Physiology 200,1296-1300, 1961). Disodium pamidronate has therefore a potent inhibitory effect on bone reabsorption and is used in the treatment of Paget's disease and of the hypercalcaemia associated with bone reabsorption due to osteoporosis, hyperparathyroidism, multiple myeloma and bone metastasis (Martindale 32nd Edition, 1999).

A crystalline and pentahydrate form of disodium pamidronate is present on the market as a medicine in reconstitutible lyophilised form (ArediatE), Novartis Pharmaceuticals Corp. ) for administration by endovenous infusion.

Different processes have been described for the preparation of disodium pamidronate.

For example, the patents US 4639338 and US 471880, in the name of Ciba Geigy, describe the preparation of a crystalline pentahydrate form of disodium pamidronate by crystallisation from an aqueous solution or by treatment of a solid form of the salt with a quantity of water necessary to obtain a crystal from crystallisation water. Such a form is proposed for oral, rectal or endovenous use.

The International patent application W00142134, in the name of Hanlim Pharm Co Ltd, describes a process for the preparation of crystalline disodium pamidronate as

a mixture of trihydrate and tetrahydrate forms. In this process the disodium pamidronate is dissolved in water, filtered, and the filtrate is crystallised at room temperature. Finally it is dried at around 75°-86°C. The product obtained is described as more stable with respect to the pentahydrate form and suitable for the preparation of injectable or soft capsule forms.

The crystalline forms described in the above-cited patents present however drawbacks which limit their use in the field of pharmaceuticals. For example, they possess a low dissolution rate which renders the preparation of liquid formulations difficult, for example for administration by injection.

On the other hand, the preparation of disodium pamidronate in amorphous form, with the aim of increasing the solubility of the active ingredient, frequently leads to highly unstable and hygroscopic products due to the increased water content.

The International patent application W00034293, in the name of Aesgen Inc., describes a disodium pamidronate in amorphous form and with a water content lower than or equal to 2%, which shows greater stability and solubility with respect to the crystalline products. However, this form of disodium pamidronate is prepared through a process of lyophilisation, which requires long times and high costs.

Therefore there is a need to develop a new process to obtain disodium pamidronate in amorphous and substantially anhydrous form that is simple, rapid and economical.

Summary of the invention The inventor has now found a new simple and economical process, for the preparation of disodium pamidronate. Such process allows the attainment of an amorphous and substantially anhydrous form of said compound which possesses an increased stability and solubility.

Description of the figures Figure 1 shows an X ray diffractogram of disodium pamidronate obtained by the process of the invention, in the operative conditions described in Example 1.

Figures 2-7 show the SEM images of the morphological analysis of disodium pamidronate obtained by: - lyophilisation. with freezing at-35°C according to the parameters claimed in

patent W00034293 (Fig. 2 secondary electrons image, magnification 300x, Fig. 3 secondary electrons image, magnification: 1500x) - lyophilisation with freezing at-23°C (Fig. 4 secondary electrons image, magnification 300x, Fig. 5 secondary electrons image, magnification: 1500x), and finally - nebulisation according to the conditions reported in Example 1 (Fig. 6 secondary electrons image, magnification 300x, Fig. 7 secondary electrons image, magnification: 1500x).

Detailed description of the invention The present invention refers to a process for the preparation of disodium pamidronate in amorphous and substantially anhydrous form characterised in that it comprises the nebulisation of an aqueous solution of disodium pamidronate having a pH comprised between 6 and 7.

Preferably, said process comprises the following steps: a) preparing an aqueous suspension of pamidronic acid; b) adding a sodium base to the suspension of step a) until reaching a pH comprised between 6 and 7, thereby obtaining a clear solution; c) filtering the solution coming from step (b); d) nebulising the solution coming from step (b).

Preferably the step a) suspension contains between 1 and 10 % w/v of pamidronic acid. Optionally the above mentioned suspension contains also mannitol, preferably in concentrations comprised between 1 and 6% w/v.

By the term"sodium base"is intended a base having a sodium ion as counterion.

Preferably said base is sodium hydroxide or sodium carbonate.

In step b) preferably said pH is comprised between 6.5 and 6.9.

Preferably, between step b) and step c) the solution is diluted with water until obtaining a concentration of sodium pamidronate comprised between 10 mg/ml and 100 mg/ml.

In step (c) the filtration is preferably performed using filters having a porosity of less than 0. 45, um Preferably, in step (d) the nebulisation is performed in a nitrogen flow. Said flow has preferably an inlet temperature comprised between 110° and 160°C and an

outlet temperature comprised between 90° and 105°C.

If the attainment of a sterile product is desired, for example for the preparation of injectable forms, the process of the invention can be carried out in a sterile environment. Furthermore, in this case the disodium pamidronate is suspended in sterile water, for example water for injectable preparation, filtered through filters having porosity of 0. 2 um and nebulised using a sterile nitrogen flow.

Alternatively, a sterile product can also be obtained by operating in non-sterile environments and sterilising the powder obtained from step d) with p or y rays.

The process of the invention is rapid and low-cost and facilitates the attainment of disodium pamidronate in amorphous and substantially anhydrous form with yields greater than 90%.

The product obtained with the above mentioned process is stable, also without the use of supports, and has a high solubilisation speed. Thanks to these characteristics it is therefore suitable to be used in the field of pharmaceuticals, in particular for injectable preparations.

In this latter case, the sterile powder obtained as described above can be repackaged into calcium free, not releasing silicon, previously depyrogenated glass vials, and sterilised in quantities of 15,30, 60 or 90 mg per vial. At the time of use the powder is dissolved in an appropriate quantity of water for injectable preparation.

The invention will now be illustrated by the following examples which are to be considered explanatory and not limiting.

Example 1 In a sterile environment, 4 g of pharmaceutical grade anhydrous pamidronic acid are suspended in approx. 50 ml of water for injectable preparation under good agitation. To the suspension a solution of 1N NaOH is then slowly added whilst constantly monitoring the pH until a clear solution having a pH of 6.8 is obtained.

The solution is then adjusted to 100 ml with water (final concentration: 47.4 mg/ml), filtered through a filter having a porosity of 0. 2, um and nebulised with a nitrogen current with an inlet temperature of 160°C and an outlet temperature of 105°C.

A white powder of disodium pamidronate is obtained with a yield of 95% by weight

comprising that recovered from the filters, which is repackaged in sterile vials in doses of 30 mg.

Example 2 The powder obtained in Example 1 has been characterised as follows. a) The disodium pamidronate titre of the product obtained has been measured by HPLC on a Lichrocart 250-4 CN column under the following operating conditions: mobile phase: 0.037 M KH2PO4, pH=3 flow rate: 0. 7mi/min wavelength : 255 nm reference standard: disodium pamidronate standard satisfying the requisites indicated by the British Pharmacopeia The titre resulted as 98.4%. b) An X-ray diffractometry has been performed using a PW1800/10 (Philips) diffractometer under the following operating conditions: radiation: Cu Kot (Kot1=1. 564060A, Ka1=1. 54439A) scanning interval : 2°-65° 20 scanning speed: 0. 02° 20/sec The diffractogram obtained, reported in Figure 1, has shown that the prepared disodium pamidronate is completely amorphous. c) The water content of the product, determined by the Karl Fischer method, has been measured as 1.6%.

The water solubility of the product has finally been evaluated which has resulted as being readily soluble.

The morphological examination was performed by SEM (Scanning Electron Microscopy) with a model IS1100A scanning electron microscope, with an acceleration voltage of 15 KV. The sample was metallised with Au with a metal thickness of around 20 nm. The photographs reported in figures 6 and 7 show that the disodium pamidronate obtained by nebulisation is constituted of spherical particles.

Example 3 In a sterile environment and under vigorous agitation 5g of pamidronic acid are suspended in 50 ml of water for injectable preparation and 1 N NaOH is added until

a solution of pH 6.7 is obtained. The volume is adjusted to 60 ml with water for injectable preparation (final concentration of 98.8 mg/ml) and filtered through a filter having a porosity of 0. 2 jim. The solution is then nebulised under a stream of nitrogen with an inlet temperature of 120°C and an outlet temperature of 95°C. A white powder is obtained, with a weight yield of 95% including the recovered material, which is repackaged into sterile vials in doses of 60 mg. The vials are immediately stoppered and ring-sealed in a nitrogen atmosphere, still working in a sterile environment.

The product obtained, analysed as described in Example 2, is completely amorphous and readily soluble and has a water content of 0.9% and a titre of 99. 1%.

Example 4 In a class B environment, 4 g of pamidronic acid were salifie in water for injectable preparation so as to obtain a clear solution having a pH of 6.9, which was filtered with a filter of porosity 0.45 Rm and nebulised in a current of nitrogen with an inlet temperature of 115°C and an outlet temperature of 93°C. A white powder is obtained with a weight yield greater than 94% including the recovered material. This is packaged in bulk, in an atmosphere of nitrogen, in a hermetically sealed container. The container was then subjected to sterilisation with ß rays.

The product has been analysed as described in Example 2 and has a disodium pamidronate titre of 98.3%, containing 1.7% water, it is totally amorphous and has good water solubility.

Example 5 In a sterile environment, with good agitation 63 g of mannitol are dissolved in 300 mi of water for injectable preparation. In the solution are suspended 4 g of pamidronic acid. 1 N NaOH is added with constant control of the pH until a pH of 6.82 is reached.

The volume is adjusted to 350 mi with water for injectable preparation (final concentration of 13.5 mg/ml of disodium pamidronate), filtered with a filter of porosity 0.2 Rm and nebulised with a nitrogen inlet temperature of 140°C and outlet temperature of 96°C. A white powder is obtained with a yield greater than 97% including the recovered material. This is repackaged into 140 sterile vials of

430 mg each, which are immediately stoppered and ring-sealed in a nitrogen atmosphere in the same sterile environment.

Example 6 In a class B environment, 5g of pamidronic acid are suspended in 50 ml of water for injectable preparation and salified with 2.25 g of NazCOs with bubbling nitrogen at pH 6.57, The solution is adjusted to 60 ml (final concentration=98. 83mg/ml) with water for injectable preparation, filtered with a filter of porosity 0.45 tim and nebulised in a nitrogen current having an inlet temperature of 155°C and an outlet temperature of 102°C. A white powder of disodium pamidronate is obtained with a yield of 95% comprising the recovered material, which is packaged in bulk, in a nitrogen atmosphere, in a hermetically sealed container. The container is then sterilised with p rays.

The product, analysed as described in Example 2 has a titre of 97.7%, is completely amorphous, contains 1.68% of water and is readily soluble.