Preparation of stabilised x-ray diagnostic composition

Abstract

The invention relates to a process for the preparation of a diagnostic X-ray composition. The composition comprises a non-ionic X-ray contrast agent in a pharmaceutically acceptable carrier. More particularly, the invention relates to a process for secondary production of X-ray compositions comprising X-ray contrast agents with a high dissolution temperature. When using the process of the invention, precipitation is avoided and degradation of the contrast agent is reduced. The process of the invention includes heat treatment of iodinated X-ray contrast agents at low pH.

Claims

1. A process for the preparation of a composition comprising an X-ray contrast agent, comprising the steps of: i) adjusting the pH of a mixture comprising the X-ray contrast agent and a liquid carrier to within a range of 2.0 and less than 4.0, by adding an aqueous acid; ii) heating the pH-adjusted mixture of step i) to 60-200° C. for a sufficient time to form a completely dissolved solution of the X-ray contrast agent in the liquid carrier that has an iodine concentration of 270-400 mg l/mL; iii) cooling the solution of step ii) to 40-60° C.; and iv) adjusting the pH of the solution of step iii) to 7.0-8.0 using a buffer to form the composition, wherein the free iodide concentration in the X-ray composition is less than 25 μg l/mL, wherein the X-ray contrast agent is Iodixanol or Compound I: ##STR00005##

2. The process of claim 1, wherein the composition comprises an amount of free iodide below 20 μg l/ml.

3. The process of claim 1, wherein the pH adjustment in step i) is carried out by adding hydrochloric acid (HCl) to the mixture.

4. The process of claim 1, wherein the pH-adjusted mixture of step i) is heated for a period of 30-240 minutes in step ii).

5. The process of claim 1, wherein the pH is adjusted in step iv) by adding buffer couple TRIS/TRIS HCl to the solution.

6. The process of claim 1, wherein sodium and calcium ions are added in the form of salts during the process.

7. The process of claim 1, further comprising any of the optional steps of filtration, dilution, filling, capsling and labeling, and heat treatment after filling.

8. A process for the preparation of an X-ray composition comprising an X-ray contrast agent, wherein the X-ray contrast agent is compound I having a formula of ##STR00006## and salts or optical active isomers thereof, the method comprising the steps of i) adjusting the pH of a mixture comprising compound I and a liquid carrier to within a range of 2.0 and less than 4.0, by adding an aqueous acid; ii) heating the pH-adjusted mixture of step i) to 110-135° C. for 30-240 minutes to form a solution of compound I in the liquid carrier that has an iodine concentration of 320-380 mg l/mL; iii) cooling the solution of step ii) to 40-60° C.; and iv) adjusting the pH of the solution of step iii) to 7.0-8.0 using a buffer to form the X-ray composition, wherein the free iodide concentration in the X-ray composition is less than 20 μg l/mL.

9. The process of claim 8, wherein the pH adjustment in step i) is carried out by adding hydrochloric acid (HCl) to the mixture.

10. The process of claim 8, wherein the pH is adjusted in step iv) by adding buffer couple TRIS/TRIS HCl to the solution.

11. The process of claim 8, wherein sodium and calcium ions are added in the form of salts during the process.

12. The process of claim 8, further comprising any of the optional steps of filtration, dilution, filling, capsuling, and labeling, and heat treatment after filling.

13. The process of claim 8, further comprising performing a heat treatment step v) after step iv).

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1: Iodide levels and end pH as a result of start pH and a heat load of 121° C. for 120 minutes, Compound 1,320 mg I/ml.

(2) FIG. 2: Iodide levels and end pH as a result of start pH and a heat load of 134° C. for 60 minutes, Compound 1,320 mg I/ml.

(3) FIG. 3: A possible production set up for the process of the invention, wherein:

(4) I denotes Water for injection (WFI)

(5) II denotes acid for pH adjustment

(6) II denotes the X-ray contrast agent

(7) IV denotes additives

(8) A denotes a mixing tank

(9) B denotes microfiltration/ultrafiltration

(10) C denotes a holding tank

(11) D denotes filling and capping

(12) E denotes autoclaving

(13) F denotes labelling and pack-off

EXAMPLES

Example 1

Stability of Compound I at Different pH

(14) Experiments were performed to investigate the level of inorganic iodide generated as a result of degeneration of Compound I as a result of a pH and heating regime. Reference is made to FIGS. 1 and 2. The heat load was controlled by using a BIER-vessel for the steam heat sterilisation. Formulated Compound I (drug product, DP, 320 mg I/ml) was added 25% HCl to obtain 4 series of 6 vials with a pH of 2.0, 3.1, 4.0 and 7.7, respectively.

(15) DP (10 ml) was filled in 10 ml vials. 3 vials from each series were autoclaved at 121° C. for 120 minutes and the remaining 3 vials were autoclaved at 134° C. for 60 minutes. The samples, including 2 reference samples, were subjected to pH and iodide analyses. The results from these studies showed that only a minor increase in iodide levels and no significant change in pH could be observed for the samples having a start pH in the range 2-4, while high iodide levels and a corresponding drop in pH was observed for the samples having a start pH of 7.7, as shown in FIGS. 1 and 2. Hence, this is a proof of concept for the process of the invention, reducing degeneration of the contrast agent when applying heat at reduced pH. These results enable a heating regime with sufficient heat load to ensure complete dissolution of any crystalline material in the bulk material, as an acceptable low level of free iodide.

Example 2

Possible Production Set Up for Secondary Production of Compound I

(16) Reference is made to FIG. 3. Compound I is dissolved in water for injection (WFI) in the mixing tank (A). HCl is used to set the unbuffered solution to pH 3-3.5. Under these conditions, Compound I is stable enough to undergo heating well above the dissolution temperature (110-111° C./330 mg I/ml) for as long as it takes to achieve complete dissolution without causing the amount of free iodide to rise significantly (e.g. at 120-180° C. for 20-240 minutes). Subsequently, the heated solution of Compound I of e.g. 330-360 mg I/ml is cooled to 40-60° C. and diluted by a solution of TRIS/TRIS-HCl of a pH of approximately 8.0 to yield the final drug product formulation containing TRIS 10 mmol/l of pH 7.4-7.7 (measured at room temperature, 20-25° C.) and Compound 1,320 mg I/ml.

(17) This dilution and pH equilibration can be done either in the mixing tank or even as a rinsing step for a subsequent ultra filtration (B) if the filters tolerate low pH or alternatively in the ultrafiltrate after ultrafiltration.

(18) If the process of the invention can be effective enough to ensure complete dissolution, ultrafiltration as a process step to remove undissolved crystals can possibly be omitted.

Example 3

Production Set Up Used for Secondary Production of 400 Litres of Compound I in a Concentration of 320 mg I/ml

(19) Reference is made to FIG. 3.

(20) 261 kg of Compound I was dissolved in 250 litres of water for injection (WFI) and added 44 g Na.sub.2Ca-EDTA.2H.sub.2O in the mixing tank (A). HCl 5M was used to set the solution to pH 3. Under these conditions, to the composition underwent heating for 40 minutes at 122° C. Subsequently, the heated solution of Compound I of approximately 340 mg I/ml was cooled to approximately 80° C. and added the remaining excipients, being 29 g of CaCl.sub.2.2.H.sub.2O, 1052 g of NaCl, 484 g of TRIS base and 346 ml of HCl 5M to yield a pH of 7.3. This solution was cooled to approximately 50° C. and filtered through a 10 kDa ultrafilter. The remaining WFI to yield a solution of 320 mg I/ml of compound I was used to rinse the ultrafilter by dilution of the concentrated retentate. The filtered solution was dispensed and autoclaved for 20 minutes at 121° C. After autoclaving, the concentration of inorganic iodide was 10 μg/ml, which is approximately a fifth of the concentration resulting from a conventional production not using the process of the invention.