The object of the present invention is a process for pre¬ paring a clodronate preparation by dry granulation, where the crystalline phase of the clodronate raw material used is the stable and easy-to-handle tetrahydrate of the clodronic acid disodium salt (CH ₂ Cl ₂ 0 ₆ P ₂ Na ₂ -4H ₂ 0) , with a de¬ finite crystal form.

Clodronate or the disodium salt of (dichloromethyle- ne)bisphosphonic acid, tetrahydrate, is useful for ins¬ tance in the treatment and prophylaxis of disorders of the calcium metabolism, such as bone resorption, hyper- calcaemia and osteoporosis. Based on its ability to form a strong complex with a Ca ²⁺ -ion, clodronate removes ex¬ cessive calcium from the circulation, prevents calcium phosphate from dissolving from the bone and/or acts via cell-mediated mechanisms. However, it is necessary to administer clodronate in relatively large doses for a prolonged time. A problem with clodronate preparations has therefore been how to achieve a sufficiently high amount and concentration of the active agent in a capsule or tablet, without having to use capsule or tablet sizes which are unpleasantly large for the patient.

Due to the properties of clodronate, it has in practice turned out that untreated clodronate raw material is dif¬ ficult to mix to a homogenous mixture with other exci- pients and active agents present in the preparation.

Processes previously used for the preparation of clod¬ ronate preparations have been disclosed for instance in the publication EP 275 468, which relates to a process for preparing a clodronate preparation by a wet granula- tion process. In the process the raw materials are mixed dry, a granulating liquid is added, the mixture is wet granulated and the granulate is dried.

Due to the properties of clodronate, the clodronate pow¬ der thus obtained is, however, inaccurate as regards its composition and obviously difficult to handle (sticky, very poor flow properties) . It is thus extremely diffi- cult in practice to mix it with other substances used in the preparation, as well as to further process it, where¬ fore for instance a relatively large amount of gliding agents is needed. From the unhomogenous raw powder an unhomogenous and poorly flowing product mass is then ob- tained, which affects also the accuracy of dosing of the final medicament.

In the absorption of clodronate, as well as of other bis- phosphonates, great individual and diet-related differen- ces have been observed, wherefore the homogenity of the drug and the pharmaceutical preparation is essential for the determination of a suitable dose and for the follow- up of the treatment.

The bulk volume of the clodronate raw material generally varies a great deal between different batches of prepara¬ tion, due to the difficultly controlled crystallization process in the preparation of the raw material, where the four crystal waters must have time to take their posi- tions in the crystal lattice in order to obtain a uniform and non-caking composition but where, on the other hand, a too slow crystallization leads to an unsuitably large crystal volume. In a wet granulation process this has the effect that the amount of granulating liquid has to be varied from one granulation batch to the next, depending on the quality of the raw clodronate, in order to obtain, as the end product, granules with the same bulk volume. As stated above, the wet granulation process is thus an extremely difficult and laborious process and the final result is often, however, unforeseeably inaccurate. The wet granulation process is always connected with time- consuming and expensive drying of the granules. In addi-

tion to the step of manufacturing the raw material, a second balancing regarding the four necessary crystal waters is required in the drying stage of the wet granu¬ lation process.

According to the invention it has now surprisingly been discovered that by crystallizing clodronate specifically in the form of stable and non-caking and non-sticky di¬ sodium clodronate tetrahydrate, having a predetermined crystal structure and size and thus predetermined proper¬ ties, and by dry granulating under controlled conditions in such a way that the crystal structure of disodium clodronate tetrahydrate is preserved, the previous prob¬ lems in the handling of clodronate, as well as the cum- bersome wet granulation process which is inaccurate as regards the end product, can be avoided. Especially the four crystal waters of disodium clodronate need to be adjusted correctly only once when this is done already during the preparation of the raw material. In the dry granulation process there is no need for readjustment of the same as in the wet granulation process. Possible dif¬ ferences between batches of raw material, even minor dif¬ ferences in the bulk volume, are evened, provided that the clodronate is composed of crystallized, stable diso- dium clodronate tetrahydrate, which is suitable for dry granulation. The result is ready-to-use granules of uni¬ form quality from batch to batch, which granules are ea¬ sily flowing and thus are well mixed with excipients to form a homogenous formulation mass.

Due to the good handling characteristics of granules ob¬ tained from the dry granulation process as such but espe¬ cially when easily filtered, stable, non-caking and non- sticky disodium clodronate tetrahydrate is used, there is not necessarily a need for excipients at all or they are needed in considerably smaller amounts than in the pre¬ vious methods. Thus the proportion of the active agent in

the preparation may be kept higher and also exactly at the desired level.

Dry granulation is thus an effective way to minimize the bulk volume of the clodronate raw material. This is par¬ ticularly of advantage when clodronate is administered in capsule form, whereby the size of the capsule may be cho¬ sen as small as possible.

The object of the present invention is thus a process for preparing a clodronate preparation, which process comp¬ rises the following steps:

- clodronate is crystallized as disodium clodronate tet¬ rahydrate from an aqueous solution of disodium clod- ronate,

- the resulting disodium clodronate tetrahydrate is dry granulated by compressing in such a way that the crystal structure of the disodium clodronate tetrahydrate is pre¬ served, and thereafter by crumbling and screening the mass to granules of a suitable size,

- the dry granulated disodium clodronate tetrahydrate is optionally mixed with suitable excipients, such as fil¬ ling agents and gliding agents and, if necessary, disin- tegrants.

In the process according to the invention, clodronate is first crystallized as disodium clodronate tetrahydrate from an aqueous solution of disodium clodronate. Due to the choice of crystallization conditions, stable disodium clodronate with four crystal waters is obtained, either as easily processable flakes or needles, or as a fine crystalline powder with good flowing properties. In both cases the composition of the crystal phase is the same (CH ₂ Cl ₂ 0 ₆ P ₂ Na ₂ 4H ₂ 0) , the crystal form being triclinic and centrosymmetric (AR PI; a = 5.911, b = 9.190, c = 11.284, a = 89.39, β = 87.36, y = 88.57, V = 612.1, Z = 2) . One of the four crystal waters is uncoordinated. One of the

sodium atoms is coordinated with one chlorine atom. The structure is composed of four-chain bundles of infinite length which are parallel with the a axis and which are connected to each other with hydrogen bridges.

Crystallization may be carried out by adding, in a cont¬ rolled manner, to an aqueous solution of disodium clod¬ ronate an organic solvent which is fully or partly water- soluble but in which disodium clodronate is poorly solu- ble, and by gradually lowering the temperature while stirring, whereby the disodium clodronate crystallizes as the tetrahydrate. As water-soluble organic solvents, for example, a water-soluble lower alcohol, such as methanol or ethanol, n-propanol, isopropanol, t-butanol, glycol, glycol ethers, tetrahydrofuran, dioxane, acetone, espe¬ cially ethanol, methanol, monomethyl and ethyl ethers of glycol, tetrahydrofuran, dioxane or acetone, come into question, and ethanol is especially preferred. As a part¬ ly water-soluble organic solvent, for example, methylene chloride, chloroform, methyl ethyl ketone, ethyl acetate, butanol, or a mixture of these and completely water-solu¬ ble solvents may be used. The starting temperature is higher than room temperature, e.g. 30-120°C, preferably 60-100°C, especially 70-90°C and most preferably about 80°C. The rate and manner of adding the solvent are to be such that clodronate does not precipitate prematurely or untimely without its crystal water molecules. After the addition the temperature is lowered. The final tempera¬ ture is 0-20°C, preferably about 15°C, to which it has been lowered from the starting temperature of 80°C. Tem¬ perature may be lowered continuously or stepwise, e.g. by keeping the temperature for a while at about 40°C.

By letting the crystallization take place at an appropri- ately slow rate as described above, disodium clodronate tetrahydrate is obtained as easily processable fine fla¬ kes or needles. The size of the crystals can be adjusted by changing the rate of addition of the organic sol-

vent component and/or the rate of lowering the temperatu¬ re.

Crystallization may also be carried out by evaporating an aqueous solution of disodium clodronate slowly so that the proportion of water is reduced, in the presence or absence of a water-soluble or partly water-soluble or¬ ganic solvent, such as mentioned above, and also in the presence of an organic solvent which is poorly soluble in water, in a two-phase system at a temperature of at least about 20 °C but no more than about 100 °C, preferably 40 - 70 °C, while the solution is stirred. If desired, the evaporation may be performed under reduced pressure, whereby the temperature may correspondingly be lower. As a water-soluble organic solvent, for example, a water-so¬ luble lower alcohol, such as ethanol, n-propanol, isopro- panol, t-butanol, glycol or glycol ether may be used. As an organic solvent which is poorly or partly water-solu¬ ble, for example methylene chloride, chloroform, methyl ethyl ketone, ethyl acetate, butanols, such as 1- and isobutanol, or a mixture of these and those mentioned above come into question, especially methylene chloride, chloroform, 1-butanol, glycol or a monomethyl or monoet- hyl ether of glycol.

Possible residues of organic solvent may be removed e.g. by washing with ethanol and drying at a temperature, at which the crystalline tetrahydrate does not yet liberate its one crystal water which is most easily released (< 50 °C) . By crystallizing this way, disodium clodronate tet¬ rahydrate is obtained as a fine crystalline powder with good handling properties.

It is advantageous to use disodium clodronate with four crystal waters as the raw material of a clodronate prepa¬ ration, which crystal form obtained in the very manner as described above, as a flake, needle and powder, is stable

and easy to handle. However, if the equilibrium is dis¬ turbed for example by removing or adding crystal waters, i.e. by heating or moistening, the drug raw material be¬ comes sticky or cakes and is thus difficult to handle. Because the first of the four crystal waters is split off relatively easily and rapidly at a temperature of > 50 °C, it is of vital importance to keep the conditions in the different stages of the manufacturing process of the pharmaceutical preparation such that the tetrahydrate structure is preserved.

Disodium clodronate tetrahydrate, which has been crystal¬ lized as described above, may be characterized by powder X-ray diffraction and single crystal X-ray diffraction. The crystal structures measured fully correspond to the published one (Nardelli and Pelizzi, Inorg. Chim. Acta 80 (1983) 289) , and thus the structure of the clodronate used in the dry granulation of the invention and of the clodronate crystallized for this purpose according to the invention is correct.

According to our invention it has been found that if the disodium clodronate crystallized as described above is dry granulated under controlled conditions, the structure of disodium clodronate tetrahydrate is preserved and den¬ se, easy-to-handle granules of uniform quality are for¬ med.

According to our invention the granulation is performed as a dry granulation whereby disodium clodronate tetra¬ hydrate is compressed, preferably between rollers, to a thin sheet or mass which is further crumbled and screened to granules of a suitable size. The dry granulation is performed under such temperature and pressure conditions that the crystal structure of the disodium clodronate tetrahydrate is preserved. When the dry granulation is carried out with a roller compactor, the compression

pressure is 30 - 90 bar, preferably 40 - 75 bar and most preferably about 50 - 65 bar. The speed of the rollers during compression is 8 - 16, preferably 8 rp . Compres¬ sion is performed at a temperature, which is close to room temperature, however, not higher than about 40 - 50 °C, preferably at 20 - 30 °C.

The granules obtained by dry granulation can, if desired, be mixed with suitable excipients, such as filling agents and gliding agents/lubricants and, if necessary, disinte- grants. According to the invention, the amount of exci¬ pients can be kept low, due to the good handling charac¬ teristics of the clodronate granule powder obtained from the dry granulation process.

The use of different excipients in the manufacture of a clodronate preparation is as such known, e.g. DE 2731366, DE 2813121, DE 3500670, EP 336851, US 3683080, US 4234645. Neither in the manufacture of clodronate prepa- rations nor in the manufacture of other known bisphospho- nate preparations has attention previously been paid to the possible role of the crystal waters.

The excipients optionally used in preparations of solid clodronate and mixtures thereof are such that do not bind or release water, in order not to disturb its tetrahydra¬ te structure.

The filling agents (weight balancing agents) to be used may be for example lactose, especially α-lactose monohyd- rate, microcrystalline cellulose, starch or its derivati¬ ves, mannitol, glucose, saccharose, or a mixture of two or more filling agents. A preferred filling agent accor¬ ding to the invention is α-lactose monohydrate, which is used in an amount necessary to adjust the amount of diso¬ dium clodronate in the preparation to the desired level. The amount of filling agent is thus about 0 - 20 % by

weight, usually about 2 - 12 % by weight, based on the weight of the final preparation.

If necessary, other excipients can also be used, for example flavouring and sweetening agents, such as natural or artificial flavourings and sweeteners, in the amounts needed.

As gliding agents the conventional gliding agents and lubricants known in the art can be used, such as stearic acid or its salts (Mg-, Ca-) , talc, starch, colloidal silica or a mixture of two more gliding agents, preferab¬ ly stearates and/or talc. The amount of gliding agent can and should be kept low, as for example the optional cal- cium or magnesium containing agents in the preparation bind clodronate by forming a complex therewith, whereby the absorption of the drug is decreased. By using the process according to the invention, the amount of gliding agents can be substantially lowered or its use can even be totally abandoned, whereby the amount of the active agent in the preparation can be kept high and its absorp¬ tion in the organism does not decrease. Thus the amount of gliding agent can be for example 0 - 10 % by weight, especially 2 - 6 % by weight, based on the weight of the final preparation.

If desired, also disintegrants can be added to the prepa¬ ration. These are disintegrants generally known in the art, such as for example microcrystalline cellulose, cross-linked sodium carboxymethylcellulose, starch or its derivative, croscarmellose, crospovidone, or mixtures of two or more disintegrants. In the process according to the invention disintegrants may be used for example about 0 - 3 % by weight, especially about 0.5 - 1 % by weight, based on the weight of the final preparation.

By using excipients one can also regulate, if desired,

whether a preparation is to decompose in the stomach or only later in the gastrointestinal tract, and also the dissolving rate. Thus the preparation can be coated with as such known film forming agents, which dissolve at the desired pH, such as for example with shellac, cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, poly- vinyl acetate phthalate, cellulose acetate trimellitate or various acryl and methacryl acid derivatives. Film forming agents are known to a person skilled in the art and are commercially available.

The obtained mixture is suitable for administration as a number of different formulations formed from crystal pha- se clodronate. Thus it can for example be filled in cap¬ sules, compressed into tablets or used as granules or a powder according to methods generally known in the art, and further coated, if desired. Especially preferred are capsules and tablets, the size of which can be kept small due to the methods of the invention.

A drug delivery form prepared by the process according to the invention preferably comprises 60 - 80 % by weight of anhydrous disodium clodronate. Preferably it contains 65 - 75 % by weight of anhydrous disodium clodronate (corresponds to about 81 - 94 % of the tetrahydrate form) , about 2 - 12 % by weight of a filler, for example lactose, about 2 - 6 % by weight of a gliding agent, for example talc or calcium stearate, and about 0 - 1 %, es- pecially 0.5 - 1 % by weight of a disintegrant, based on the weight of the final preparation.

Representative compositions prepared according to the invention are (% by weight) :

Anhydrous clodronate 60 65 77.2 78.4 80

Crystal water 15 16.2 19.3 19.6 20

Others altogether 25 18.8 3.5 2 0 whereof

Filling agent 18 15 2 2 0

Gliding agent 4 2.8 1 0 0

Disintegrant 3 1 0.5 0 0

Total 100 100 100 100 100

The following examples illustrate the invention without limiting the same.

Example 1.

200 kg of raw clodronate is dissolved in 600 kg of water by heating to 70 - 80 °C. The pH is adjusted to 3.1 with 1-N hydrochloric acid. 320 kg of ethanol is poured into the solution during 30 - 40 minutes. The mixture is coo- led using circulating water cooling to 35 - 45 °C and by cold sol cooling to 10 - 15 °C. The crystal mass is cent- rifuged and washed with 10 % water-ethanol mixture. The spin-dry product is wet-screened and dried at 30 °C. The dried product is mixed, screened and bottled. The yield is 190 kg of disodium clodronate tetrahydrate with a bulk density of 0.25-0.45 g/ml.

The resulting disodium clodronate tetrahydrate was dry granulated by compressing in a roller compactor under a pressure of about 60 bar at room temperature (20-25 °C) until a suitable bulk density was achieved. The desired bulk density was typically obtained with a granule size over 0.5 mm.

Capsules were prepared with the following composition per capsule:

Disodium clodronate

(calculated as anhydrous) 400.00 mg

Talc 22.80 mg

Calcium stearate 2.85 mg

Anhydrous colloidal silica 2.85 mg

Lactose ad 570.0 mg 41.50 mg

The disodium clodronate concentration (as anhydrous) of the composition is thus 70.2 % by weight. Granules of dry granulated disodium clodronate tetrahydrate were mixed with calcium stearate, talc, anhydrous silica and lacto¬ se. The mixture was filled into capsules (size no. 1) .

Example 2.

Disodium clodronate tetrahydrate was dry granulated as described above. Capsules were prepared with the follo¬ wing composition per capsule:

Anhydrous disodium clodronate 400.00 mg Lactose ad 570.00 mg 70.00 mg

Dry granulated disodium clodronate tetrahydrate and lac¬ tose were mixed and the mixture was filled in capsules no. 1.

Example 3.

Disodium clodronate tetrahydrate was dry granulated as described above. Capsules were prepared with the follo¬ wing composition per capsule:

Anhydrous disodium clodronate 400.00 mg

Talc 22.80 mg

Anhydrous colloidal silica 2.85 mg

Lactose ad 570.00 mg 45.15 mg

Dry granulated disodium clodronate tetrahydrate, talc, anhydrous silica and lactose were mixed and the mixture was filled into capsules no. 1.

Example 4.

Disodium clodronate tetrahydrate was dry granulated as described above. Tablets were prepared with the following composition per tablet:

Anhydrous disodium clodronate tetrahydrate 400.00 mg

Sodium croscarmellose 10.00 mg

Anhydrous silica 10.00 mg

Magnesium stearate 5.20 mg Microcrystalline cellulose ad 650 mg 124.80 mg

Dry granulated disodium clodronate tetrahydrate, sodium croscarmellose, anhydrous silica and microcrystalline cellulose were mixed into a homogenous mixture. Thereaf- ter magnesium stearate was added to the mixture and stir¬ red. The obtained powder mixture was tabletted using pun¬ ches of a suitable size, for example round, concave pun¬ ches with a diameter of 12 mm, to a suitable strength, for example to 7 - 9 kg.

Example 5.

Disodium clodronate tetrahydrate was dry granulated as described above. Dosage powders were prepared to be taken as such or to be mixed with water. The composition of the powder per sachet was as follows:

Anhydrous disodium clodronate tetrahydrate 400.00 mg

Aspartame 25.00 mg Flavouring: e.g. lemon 31.25 mg

Magnesium stearate 3.75 mg

Mannitol ad 625 mg 65.00 mg

Dry granulated disodium clodronate tetrahydrate, asparta- me, flavouring and mannitol were mixed into a homogenous mixture. Then magnesium stearate was added and mixed. The powder mixture was filled into sachets of a suitable si- ze.

Example 6.

Coated granules: Disodium clodronate tetrahydrate was dry granulated as described above. The granules were coated with an enteric film in an air suspension apparatus. The composition of the coating:

Methyl hydroxypropyl cellulose phthalate 8.3 %

Diethyl phthalate 0.8 %

Ethanol (96 %) 72 %

Purified water 18.9 %

The coated granules may be filled into capsule shells or suitable sachets.