HK1116054B - A process for the preparation of a piroxicam: betacyclodextrin inclusion compound - Google Patents

Description

Process for preparing piroxicam beta-cyclodextrin inclusion compound

Technical Field

The present invention relates to a process for the preparation of an inclusion complex of piroxicam with beta-cyclodextrin by spray drying, for application on a pilot plant scale or on an industrial scale.

More specifically, the present invention relates to the preparation of piroxicam in a ratio of 1: 25: a method for the production of beta-cyclodextrin inclusion complexes having optimal physico-chemical properties and process and biopharmaceutical properties for the preparation of solid pharmaceutical compositions for oral administration.

Background

Piroxicam is a type of nonsteroidal anti-inflammatory drugs (NSAIDs) that are widely used in rheumatoid arthritis, osteoarthritis, acute pain in musculoskeletal disorders, postoperative and post-traumatic pain, and dysmenorrhea.

Piroxicam is poorly soluble in water (0.003% at pH 5, 37 ℃) and exhibits low surface wettability (water contact angle 76 ℃) and high lattice energy as evidenced by its melting point (198-.

Since piroxicam molecules exhibit good membrane penetration characteristics, their low solubility results in slow dissolution rates in gastrointestinal fluids, thereby resulting in slow absorption and delayed onset of action.

Slow dissolution may also exacerbate local side effects associated with the drug (e.g., gastric irritation).

The operational control of piroxicam is complicated by its possible tautomeric transformations and polymorphism. Said molecules can in fact exist in two polymorphic forms, a and β, having the same intramolecular structure eze (i) and different intramolecular-and intermolecular hydrogen bonding interactions, and in the pseudopolymorph, which is a hydrate of the zwitterionic form ZZZ, one of its possible resonance forms is represented by the general formula (II):

an effective method for overcoming the problems associated with low solubility of piroxicam relies on the preparation of inclusion complexes with cyclodextrins as described in EP 153998. The terms complex, inclusion complex and clathrate are used synonymously hereinafter.

Cyclodextrins (CDs) are natural cyclic oligosaccharides with a bulge-like macrocyclic shape obtained by enzymatic degradation of starch. The three major cyclodextrins consist of 6 (. alpha.), 7 (. beta.) or 8 (. gamma.) (1 → 4) D-glucopyranoside units. Among these, β CD appears to be the most useful in the combination of piroxicam.

The solubilization kinetics of piroxicam in water released from the inclusion complex with β -cyclodextrin in a preferred molar ratio of 1: 2.5 is the fastest among any other piroxicams obtained by any process modification of the crystalline forms known so far.

By solubilization kinetics we mean the time to reach the maximum piroxicam dissolution concentration after dispersion of the inclusion complex in powder form into water.

Having the formula C₁₅H₁₃N₃O₄S*2.5*C₄₂H₇₀O₃₅And 1: 2.5 piroxicam with molecular weight of 3168.912: the beta-cyclodextrin inclusion complex (hereinafter 1: 2.5P beta CD) is also referred to as CHF 1194.

1: 2.5P β CD clathrate, like piroxicam, exhibits anti-inflammatory, analgesic and antipyretic properties. As an analgesic, it is specified for the treatment of diseases such as toothache, post-traumatic pain, headache and dysmenorrhea. It is administered by oral route in the form of tablets or granules, preferably tablets.

Preliminary clinical and clinical studies have demonstrated that oral absorption of piroxicam from 1: 2.5P β CD tablets and granules is more effective than oral absorption from piroxicam capsules.

In particular, the bioavailability of the active ingredient is significantly improved in terms of the rate and extent of absorption over the first 2 hours.

As a result of the rapid absorption, the piroxicam action in the 1: 2.5P β CD complex is more rapidly effective, making the product particularly effective as an analgesic. It has been observed that in order to ensure an optimal profile in terms of dissolution rate and thus rapid absorption of piroxicam after administration of 1: 2.5P β CD tablets, the coarse powder material should be able to produce a dissolution concentration of piroxicam equal to or higher than 0.4g/100ml (0.4% w/v) within the first 15 minutes after dispersion in water.

The successful results obtained with cyclodextrins rely on the following facts: by compounding, a stable amorphous structure can be obtained; since the amorphous form has a large surface area and its lattice energy is much lower than that of the crystalline form, the wettability and water solubility of piroxicam are increased. In fact, such amorphous piroxicam is a metastable form that crystallizes within a few hours. Furthermore, Raman studies have also demonstrated that piroxicam in the beta-cyclodextrin inclusion complex is presumed to have a zwitterionic structure with delocalized positive and negative charges similar to hydrate pseudopolymorph (II). The structure is stabilized by chemical interaction with beta-cyclodextrin via electrostatic and hydrogen bonds. The bipolarity of the zwitterionic structure improves the solubilization kinetics and instant solubility of piroxicam.

Since the solubilization kinetics of piroxicam in water also depend on the intramolecular structure presumed for piroxicam in the 1: 2.5P β CD inclusion compound, the relevant preparation method should be able to achieve complete conversion of the zwitterionic form of piroxicam.

Furthermore, the preparation method should be able to complete the inclusion reaction and complete amorphization of the entire product.

On the other hand, amorphous active substances may be subject to the risk of crystallization during storage due to the presence of residual water. Once an amorphous material is formulated into a solid pharmaceutical preparation form such as a tablet, the crystallization may cause phenomena such as swelling or loss of hardness of the tablet. It is therefore also of great importance that the preparation process yields amorphous material in which the amount of residual water is as minimal as possible and is equal to or lower than 5% w/w, preferably equal to or lower than 4% w/w, in respect of 1: 2.5P β CD.

In summary, a preparation method suitable for preparing a 1: 2.5P β CD clathrate in powder form should result in:

i) the two components, namely piroxicam and beta-cyclodextrin, are not significantly degraded;

ii) the inclusion reaction is complete;

iii) complete amorphization;

iv) complete conversion of piroxicam to the zwitterionic form;

v) the amount of residual water is equal to or lower than 5% w/w, preferably equal to or lower than 4% w/w.

Furthermore, the method should provide a 1: 2.5P β CD which is capable of producing a dissolution concentration of piroxicam equal to or higher than 0.4g/100ml (0.4% w/v) within the first 15 minutes after dispersion of the powder in water.

As mentioned above, when 1: 2.5P β CD is used for the preparation of solid pharmaceutical formulations for oral administration and in particular tablets, the latter properties are of primary importance for ensuring optimal performance in terms of piroxicam dissolution rate.

Prior Art

The cyclodextrin inclusion complex can be prepared by reaction between solid or semi-solid or liquid ingredients.

In the solid state process, the two ingredients may optionally be screened to make the particle size uniform and thoroughly mixed, after which they are milled in a high energy mill with optional heating. Screening and homogenizing.

In the semi-solid state, the two components are kneaded in the presence of a small amount of a suitable solvent and the resulting compound is dried, screened and homogenized.

Generally, liquid complex formulations are formed by dissolving the cyclodextrin and drug in a suitable solvent and then isolating the solid complex by crystallization, evaporation, spray drying or freeze drying (lyophilization).

In particular, freeze drying and spray drying are processes that can be applied on an industrial scale.

Freeze-drying is a process of removing water from a product by sublimation, i.e., at a product temperature below its eutectic temperature.

In WO 03/105906, the Applicant describes a process for the preparation of 1: 2.5P β CD by freeze-drying on an industrial scale, in which a dilute aqueous solution of the two components piroxicam and β -cyclodextrin is subjected to a freezing process at an extremely high rate before drying.

Although the freeze-drying process is extremely convenient for potentially thermolabile molecules such as piroxicam and β -cyclodextrin due to unplanned heating, freeze-drying involves a considerable time step to remove large amounts of water by sublimation.

Spray drying may constitute an alternative method of removing water from the product. It can be faster than freeze-drying but requires heating, which makes the process somewhat disadvantageous for application to potentially thermolabile molecules such as piroxicam and β -cyclodextrin.

Spray drying is essentially carried out by atomizing a preheated solution, preferably an aqueous solution, into a drying chamber of a spray dryer apparatus in which small droplets are contacted with a hot gas stream of controlled temperature and converted into powder particles. As the powder is discharged from the drying chamber, it passes through a powder/gas separator, such as a cyclone, where it is further dried and collected.

The parameters that can be adjusted to obtain a powder with well-defined characteristics are: i) the type of atomization device; ii) the inlet gas temperature for drying the spray material in the drying chamber (hereinafter referred to as inlet temperature); iii) gas flow rate; and iv) the flow rate of the feed solution (hereinafter referred to as feed flow rate). Another important parameter affecting the final humidity of the powder is the temperature of the drying gas leaving the spray drying chamber (hereinafter referred to as the outlet temperature).

The preparation of inclusion complexes of piroxicam with cyclodextrins by spray drying on a laboratory scale is mentioned in several documents of the prior art. However, no experimental conditions are disclosed, or, although disclosed, they are not suitable for the preparation of 1: 2.5P β CD clathrates which meet the above requirements.

EP153998 generally discloses that piroxicam and cyclodextrin complexes comprising a molar ratio of 1: 1 and 1: 10 can be prepared in different ways:

a) by crystallization from water or an organic/aqueous solution containing both components;

b) by evaporation of the water/ammonia solution;

c) by freeze drying or atomizing the water/ammonia solution in a gas stream (spray drying).

All examples refer to the preparation of laboratory scale 1: 2.5P β CD (from mg to g). The conditions under which the product is obtained by spray drying are not reported.

EP 449167 discloses a process for the preparation of inclusion complexes of piroxicam with β -cyclodextrin, characterized in that the two components, both in powder form, are mixed with each other and then co-milled in a high-energy mill whose milling chamber has been saturated with steam. In example 2 of EP 449167, the dissolution rate of tablets containing 1: 2.5P β CD prepared according to the claimed process as active ingredient was compared with the dissolution rate of similar pharmaceutical compositions containing the same active ingredient obtained by different methods, including spray drying, and with the dissolution rate of a commercially available piroxicam composition in capsule form. The conditions under which the product is obtained by spray drying are not reported.

In Acerbi D et al (Drug Invest 1990, 2, supply.4, 29-36), a flow chart depicting the process of preparing 1: 2.5P β CD is shown. For the spray drying process involved, no other conditions than the aqueous beta CD solution temperature (65 ℃ C. -70 ℃ C.) prior to introduction into the apparatus were reported. Furthermore, as can be understood from fig. 7, the maximum piroxicam dissolution concentration produced within the first 5 minutes after dispersion in water by spray drying of the 1: 2.5P β CD powder obtained by processing the solubilization profiles of piroxicam from complexes prepared using different methods is only about 0.03g/100ml of water (0.03% w/v).

Pezoa R et al (Proceedings of the 6^thInternational conference Pharmaceutical Technology, 1992, 6 months 2-4 days, Paris) reported characterization of 1: 1P β CD complexes obtained by freeze-drying and spray-drying methods. No experiment of freeze-drying has been reportedConditions, also no experimental conditions for spray drying were reported. In this paper, it is generally described that the dissolution profile of hard gelatin capsules containing spray-dried complexes shows a significant increase in dissolution rate, but lower than those of hard capsules containing freeze-dried complexes.

Pavlova A V et al (Analyt Lab 1995, 4, 87-91) relate to the analytical characterization of 1: 2.5P β CD inclusion complexes prepared in different ways. Among other methods, inclusion complexes prepared by spray drying have been reported, but conditions have not been reported.

A comparative study of the dissolution profiles of inclusion complexes of piroxicam with beta-cyclodextrin prepared by different methods was reported in Van Hees T et al (proceedings of the Ninth International symposium on Cyclodextrins, Kluwer, 1999, 211-214). By supercritical CO₂Freeze drying and spray drying to prepare the compound. The conditions under which the product is obtained by spray drying are not reported. Dissolution or solubilization kinetics were determined on the spray dried material in a USP XXIII n.2 dissolution apparatus using 500ml of solution at pH 1.2 and pH 6.8. In the first 15 minutes, very small amounts of about 30mg and about 50mg of piroxicam were dissolved per 100ml, corresponding to concentrations of 0.03% and 0.05% w/v.

In Kata M et al (Proceedings of the 10^thInternational Cyclodextrin Symposium, Wacker, 2000, 629-634), four different molar ratios (2: 1, 1: 2 and 1: 3) of piroxicam were prepared by spray drying using a laboratory scale instrument (Niro Minor atomizer): an inclusion compound of beta-cyclodextrin. The powder mixture was dissolved in dimethylformamide and water and spray dried under the following conditions: feeding flow rate: 600ml/h (i.e., 0.6 l/h); inlet air temperature: 155 ℃; outlet air temperature: 90 ℃; pressure: 3atm (equivalent to about 3 bar).

In Lin S-Y et al (Int J Pharm 1989, 56.249-259), 1: 1P β CD was prepared by spray drying under the following conditions: inlet temperature: 145 +/-1 ℃; outlet temperature: 75 +/-1 ℃; dry (gas) flow rate: 0.37m³/min(i.e., about 22 kg/h); atomization air pressure: 1.0kg/cm²(i.e., about 1 bar); sample feed (feed flow): 4.5ml/min (i.e. 0.27 l/h). The product formed amorphous. The dissolution rate tested using the USP XXI paddle dissolution method at a rotation speed of 50r.p.m. and at a temperature of 37 ℃ on tablets prepared using the spray dried product was faster than the dissolution rate of the physical mixture and the pure drug, as can be appreciated from figure 6(a), only about 20% of the amount of piroxicam was released after 30 minutes.

In the Kata M and Lin S-Y processes, the exit temperature is 90 ℃ or below 90 ℃.

As reported on page 4 of the present application, a 1: 2.5P β CD solid material used for the preparation of pharmaceutical formulations such as tablets should have a residual water equal to or lower than 5% w/w.

According to the applicant's findings, outlet temperatures such as the one reported in the above paper are too low to obtain a product meeting the specifications.

Thus, Kata M and Lin S-Y disclose conditions unsuitable for preparing 1: 2.5P β CD that meet the above requirements in terms of residual water and solubilization kinetics.

The use of supercritical carbon dioxide in the preparation of 1: 2.5P beta CD inclusion compounds was investigated by Van Hees T et al in Pharm Res 1999, 16, 1864-1870. For comparison, a laboratory scale instrument "Niro Portable Mini (TM) spray dryer" was also used, and 1: 2.5P β CD was prepared by applying the following conditions: the inlet temperature was 175 ℃, the feed rate was 15ml/min (i.e.0.9 l/h) and the spray pressure was 0.2-0.3MPa (corresponding to 2-3 bar).

In Table II, the results for the spray dried 1: 2.5P β CD demonstrate that water is included in an amount of 4.4%. However, the relevant gas flow and outlet temperature are not mentioned in the paper, and these parameters are of primary importance in obtaining a 1: 2.5P β CD complex capable of ensuring the desired solubilization kinetics of piroxicam.

In accordance with the prior art, it would be highly advantageous to provide a process for the preparation of 1: 2.5P β CD inclusion complex by spray drying in a manner that is applicable on a pilot plant scale or an industrial scale, said process being capable of producing:

i) the two components, namely piroxicam and beta-cyclodextrin, are not significantly degraded;

ii) the inclusion reaction is complete;

iii) complete amorphization;

iv) complete conversion of piroxicam to the zwitterionic form;

v) the amount of residual water is equal to or lower than 5% w/w, preferably equal to or lower than 4% w/w.

Furthermore, it would be even more advantageous to provide a spray drying process that produces a 1: 2.5P β CD clathrate that is capable of producing a piroxicam dissolution concentration equal to or higher than 0.4g/100ml (0.4% w/v) within the first 15 minutes after dispersion of the powder into water.

Object of the Invention

The present invention relates to a process for the preparation of 1: 2.5 piroxicam: beta-cyclodextrin (1: 2.5P β CD) inclusion compounds by spray drying, which process comprises the following steps:

i. dissolving piroxicam and beta-cyclodextrin in hot water in the presence of ammonium hydroxide in a molar ratio of 1: 2.5;

passing the resulting aqueous solution through an atomizing device to form droplets for delivery into a drying chamber of a spray dryer;

directing a preheated drying air stream into a drying chamber to form powder particles;

further drying and separating the powder particles from moisture;

characterised in that in step iii) the temperature of the inlet drying gas (inlet temperature) comprises 165-200 ℃ and the temperature of the outlet drying gas (outlet temperature) comprises 105-130 ℃.

We have found that in order to obtain a 1: 2.5P β CD clathrate meeting the above requirements, it is necessary to strictly control the inlet and outlet temperatures within the drying chamber.

In particular, we have found that by applying an inlet temperature above 200 ℃, it is not possible to obtain an dissolution concentration of piroxicam equal to or higher than 0.4g/100ml within the first 15 minutes after dispersion of the 1: 2.5P β CD powder into water. On the other hand, we have found that if the outlet temperature is below 105 ℃, residual water amounts below 5% w/w cannot be obtained. Therefore, the inlet temperature should be set at least 165 ℃, and the outlet temperature in the drying chamber should be equal to or higher than a critical value of 105 ℃ after appropriate adjustment of other parameters, such as the flow rate of the feed aqueous solution and the gas flow rate.

By operating within the temperature range of the present invention, piroxicam maintains chemical stability and no significant degradation products of 1: 2.5P β CD are observed.

The invention also relates to a pharmaceutical composition comprising as an active ingredient the 1: 2.5P β CD clathrate obtainable by the above method.

Detailed Description

The features of the process of the present invention for the preparation of 1: 2.5P β CD clathrate by spray drying, either on a pilot plant scale or an industrial scale, will become more apparent from the detailed description that follows.

By pilot plant scale or industrial scale we mean that at least 10kg, preferably 10kg to 300kg, of the batch is prepared.

Spray dryer apparatus of various sizes and configurations available as commercial suppliers may be used. The schematic in figure 1 shows a schematic of a typical spray drying apparatus.

In the first step, piroxicam and β -cyclodextrin are added together with ammonium hydroxide in a molar ratio of 1: 2.5 to a tank containing water at a temperature above 60 ℃, preferably above 70 ℃, more preferably 70-80 ℃, and then mixed until dissolved. Advantageously, the concentration of piroxicam in water should be about 2% w/v and the concentration of beta-cyclodextrin should be about 17% w/v. It is advantageous to add concentrated ammonium hydroxide, preferably at a concentration of 28-30% w/w and in a ratio of 1: 1 to piroxicam.

In the second step, the hot solution is loaded into the drying chamber (7) of the spray dryer by means of the atomizing device (2) with a fluid pump (1 in fig. 1).

In an embodiment of the invention, a pressure atomization device is used and the process parameters of the spray dryer are adjusted accordingly in order to obtain an outlet temperature of 105-130 ℃.

The pressure atomization means may consist of single or multiple nozzles through which the solution is compressed by a pump to disperse into droplets. When using a pressure atomization device consisting of a single nozzle, it is advantageous if the nozzle pressure comprises from 10 to 350 bar, preferably from 20 to 200 bar. In general, the nozzle should have an internal diameter of 0.5-0.7 mm.

In the case of a spraying method, other types of atomization devices may be used, such as rotary (centrifugal) atomization devices or other suitable devices. Those skilled in the art can employ various process conditions and parameters accordingly.

For example, a rotary (centrifugal) atomizer is a rotating disk equipped with radial or curved plates that rotate at high speeds, typically 15000-25000 r.p.m. The solution was delivered to near the center and spread between two plates, accelerating it to a high linear velocity before it exited the disc in the form of a droplet.

In the drying chamber, the droplets encounter the hot gas stream and they lose their moisture very quickly while still being suspended in the drying gas. Although there is no particular limitation on the gas used for drying the spray solution, it is advantageous to use air, nitrogen or an inert gas, preferably air, more preferably with a residual moisture content of 7000p.p.m or less. The gas is electrically heated (5) and may be introduced through a suitable distributor (6).

The heated gas stream can flow simultaneously with the liquid droplets, but convection, cross-flow, or other gas flow configurations can also be used.

Advantageously, the inlet temperature in the drying chamber of the spray dryer is varied between 165 ℃ and 200 ℃, more advantageously between 170 ℃ and 200 ℃, preferably between 175 ℃ and 195 ℃, more preferably between 178 ℃ and 182 ℃.

The exit temperature in the drying chamber should comprise 105 ℃ to 130 ℃, preferably 110 ℃ to 120 ℃, even more preferably 112 ℃ to 115 ℃.

To prepare an amount of about 10kg of inclusion complex, the spray drying method of the invention is carried out by applying a feed flow of at least 12kg/h (about 12 l/h). For higher quantities, the feed rate should comprise from 12kg/h to 200 tons/h, preferably from 12kg/h to 300 kg/h.

Advantageously, the flow rate of drying gas is at least 80Kg/h, preferably 100Kg/h, more preferably 300Kg/h, even more preferably at least 600 Kg/h.

For higher quantities, the gas flow should comprise 600kg/h to 30 tons/h.

Once the inlet and outlet temperatures provided by the present invention are determined, other process parameters should be appropriate and adjusted to each other by one skilled in the art based on batch size.

In the examples below, for a batch of about 10kg 1: 2.5P β CD, an inlet temperature of 178-182℃, a 0.5mm nozzle with a pressure of 21 bar, a flow rate of 12kg/h (about 12l/h) and an air flow rate of 600kg/h were used in order to obtain a suitable outlet temperature of 112-115℃.

Advantageously, the difference between the inlet and outlet temperatures comprises from 45 ℃ to 95 ℃, preferably from 65 ℃ to 75 ℃.

The powder is dried and separated from the wet gas by centrifugation in a rotary separator (8). When the powder particles and gas mixture enter the rotating separator, a centrifugal effect is created due to the significant increase in gas velocity. The dense powder particles are pressed against the walls of the rotating separator and the product is collected on a container (9) in the rotating separator by a discharge means, such as a rotary valve. The lighter humidified gas particles are sucked out through the exhaust pipe by means of an aspirator (10).

Alternatively, the separation is performed by using a filter medium such as a membrane medium (filter bag), a sintered metal fiber filter membrane, or the like.

In the amorphous 1: 2.5P β CD clathrate obtainable by the process of the present invention, piroxicam exists completely in zwitterionic form and can be characterized by its raman spectrum, X-ray powder diffraction pattern and thermal properties as reported in PCT application WO 03/105906.

The FT-Raman spectrum obtained by simply filling the powder into the cup showed the following peaks at 1650-^-1Characteristic main peak in the range (accuracy. + -. 1 cm)^-1)：1613cm^-1(sh)，1593(s)，1578(s h)，1561(w)，1525(br)，1519(br)，1464(m)，1436(m)，1394(s)，1331(brm)/1306(sh)，1280(w)，1260(w)，1234(w)，1217(vw)，1186(w)，1158(m)，1119(m)，1083(w)，1053(w)，1036(w)，992(w)，947(brw)。

The following drawings: sh is acromion; s is strong; m is medium; w is weak; vw is extremely weak; br is broad, brm medium broad, brw weak broad.

The amount of residual water in the 1: 2.5P β CD obtainable by the process of the present invention can be determined by the Karl-Fisher method and it should be equal to or lower than 5% w/w, preferably equal to or lower than 4% w/w. Since 1: 2.5P β CD tends to absorb water, the measurement should be carried out once the product is obtained and in any case the entry of moisture is prevented.

The solubilisation kinetics of piroxicam from 1: 2.5P β CD should be determined according to the dispersion powder method reported in example 2 below.

Advantageously, the dissolution concentration of piroxicam within the first 15 minutes should be equal to or higher than 0.4% w/v, preferably equal to or higher than 0.5% w/v.

The 1: 2.5P β CD obtained with the process of the invention can be advantageously used to prepare pharmaceutical compositions having analgesic, anti-inflammatory and antirheumatic activity, preferably in the form of tablets, effervescent tablets or sachets for oral administration, more preferably in the form of tablets, for oral administration.

Advantageously, tablets for oral administration contain per unit dose 50mg-200mg of 1: 2.5P β CD complex, preferably 95.6mg or 191.2mg (corresponding to 10 and 20mg piroxicam, respectively), mixed with suitable excipients such as lactose, crospovidone, sodium starch glycolate, silicon dioxide, starch and magnesium stearate.

The following examples will better illustrate the invention.

EXAMPLE 1 preparation of 1: 2.5P β CD by spray drying

About 50 liters of water was poured into the tank and heated to a temperature of 73-75 ℃.

8.6kg (7.57 moles) of beta-cyclodextrin, 1kg (3.02 moles) of piroxicam and 1kg of 28% ammonium hydroxide were added in succession and the mixture was stirred for 30 minutes. The solution was filtered using a 55 μm filter and loaded into a spray dryer Niro. The following process parameters were used: nozzle diameter: 0.5 mm; nozzle pressure: 21 bar; gas flow rate: 600 kg/h; feeding flow rate: 12kg/h (about 12 l/h); inlet temperature: 182 ℃; outlet temperature: 113 ℃.

The 1: 2.5P β CD product was collected as a free flowing powder in a rotary separator via a rotary valve.

The resulting product exhibited the caloric profile and raman spectra reported in figures 2 and 3, respectively, which are typical of 1: 2.5P β CD, where a complete inclusion complex reaction had occurred and piroxicam was present in zwitterionic form. Powder X-ray analysis showed a diffusion diffraction pattern typical of amorphous products. After HPLC analysis no significant amount of degradation products of piroxicam was detected.

The amount of water remaining was 3.8% w/w as determined by Karl Fischer method.

Example 2 increase of piroxicam from 1: 2.5P β CD prepared in example 1 Kinetic Properties of solution

Solubilization kinetics were determined according to the dispersed powder method.

In a dissolution tester Sotax a76, 250ml of water was introduced and the temperature was set at 37 ℃ ± 0.5 ℃. Then 20g P β CD obtained in example 1, corresponding to about 2g piroxicam, was added and the resulting dispersion was maintained under stirring at 125 r.p.m. After 15 minutes, an aliquot of the solution was withdrawn and filtered. The piroxicam dissolution concentration measured by UV spectrophotometry reached 0.5g/100ml, i.e. 0.5% w/v.

Claims (13)

1. A process for the preparation of a 1: 2.5 piroxicam: β -cyclodextrin inclusion compound comprising the steps of:

i. dissolving piroxicam and beta-cyclodextrin at a molar ratio of 1: 2.5 in hot water in the presence of ammonium hydroxide to a temperature above 60 deg.C;

passing the resulting aqueous solution through an atomizing device to form droplets for delivery into a drying chamber of a spray dryer;

directing a stream of drying gas into a drying chamber to form powder particles;

further drying and separating the powder particles from moisture;

characterized in that in step iii) the temperature of the inlet drying gas, i.e. the inlet temperature, is 165-200 ℃, and the solution feed flow rate and the flow rate of the drying gas of step ii) are suitably adjusted such that the outlet drying gas temperature, i.e. the outlet temperature, is 105-130 ℃.

2. The process of claim 1, wherein the solution feed rate of step ii) is at least 12 kg/h.

3. The method of claim 1 or 2, wherein the flow rate of the drying gas is at least 600 kg/h.

4. The process according to claim 1, characterized in that the inlet temperature is 175 ℃ to 195 ℃.

5. The process according to claim 4, characterized in that the inlet temperature is 178 ℃ to 182 ℃.

6. The process according to claim 1, characterized in that the outlet temperature is between 110 ℃ and 120 ℃.

7. The process of claim 6, characterized in that the outlet temperature is in the range of 112 ℃ to 115 ℃.

8. The process according to claim 1, characterized in that the atomizing device is a rotary (centrifugal) atomizer.

9. The process according to claim 1, characterized in that the atomizing device is a pressure atomizer.

10. The process of claim 1 wherein the temperature of the water is greater than 70 ℃.

11. The process of claim 1, wherein the temperature of the water is from 70 ℃ to 80 ℃.

12. The method according to claim 1, wherein ammonium hydroxide is used in step i) in a concentration of 28-30% and in a ratio of 1: 1 relative to piroxicam.

13. 1: 2.5 piroxicam: β -cyclodextrin inclusion compound obtainable by the process as described in any of claims 1 to 12, characterized in that the water content is equal to or lower than 5% w/w and in particular having the following properties at 1650-^-1Accuracy of characteristic FT-Raman spectral peak within range + -1 cm^-1：

1613cm^-1Acromion, 1593 strong, 1578 acromion, 1561 weak, 1525 acromion, 1519 acromion, 1464 medium, 1436 medium, 1394 strong, 1331 medium acromion/1306 acromion, 1280 weak, 1260 weak, 1234 weak, 1217 very weak, 1186 weak, 1158 medium, 1119 medium, 1083 weak, 1053 weak, 1036 weak, 992 weak, 947 weak acromion.