APPARATUS BUFFER AND METHOD FOR PH CONTROL

Abstract

An apparatus, buffer solutions and a method are provided for pH control of in vitro dissolution tests used to monitor the drug release rate from solid unit dosage forms which are used to predict their in vivo effects or for quality control purposes. A method of preparing a continuous condition and a clear bicarbonate ion based solution for in vitro dissolution testing of pharmaceutical products is also provided.

An enclosure device is also provided for use in the provision of pH control and stabilization to a bicarbonate based solution used in the in vitro dissolution testing of pharmaceutical products.

Claims

1-15. (canceled)

16. An enclosure device for use in the provision of pH control and stabilization to a bicarbonate based solution used in the in vitro dissolution testing of pharmaceutical products, comprising: a plate attached to a ring-shaped chamber, the ring-shaped chamber comprising a hollow cavity, wherein the plate comprises at least one aperture that extends through an entire thickness of the plate, the at least one aperture being configured to be connected at one end thereof to at least one supply of gas and at the other end to connect into the hollow cavity of the ring-shaped chamber, and wherein a plurality of orifices extend from the hollow cavity in a direction away from the plate through the entire thickness of the ring-shaped chamber.

17. The enclosure device as claimed in claim 16, wherein the plate comprises two or more apertures that extend through the entire thickness of the plate.

18. The enclosure device as claimed in claim 16, wherein the at least one aperture is configured to be connected to a supply of gas by connecting a tube into at least one aperture.

19. The enclosure device as claimed in claim 18, wherein a diameter of the tube is 1-10 mm.

20. The enclosure device as claimed in claim 16 through which a gas can be supplied which, when dissolved into the bicarbonate solution, will increase or decrease a pH thereof.

21. The enclosure device as claimed in claim 16, wherein the at least one aperture is configured to be connected to a supply of gas at one end thereof.

22. The enclosure device as claimed in claim 16, wherein a distance between each of the plurality of orifices is in a range of 1-150 mm.

23. The enclosure device as claimed in claim 16, wherein a diameter of each of the plurality of orifices is 0.1-2 mm.

24. The enclosure device as claimed in claim 16, wherein an angle at which each of the plurality of orifices passes through the ring-shaped chamber is in a range of 45-90 relative to a horizontal plane of the plate.

25. The enclosure device as claimed in claim 24, wherein the angle at which each of the plurality of orifices passes through the ring-shaped chamber is the same.

26. The enclosure device as claimed in claim, wherein the angle at which each of the orifices passes through the ring-shaped chamber is different.

27. The enclosure device as claimed in claim 16, wherein the ring-shaped chamber is in a shape of a circle or an oval.

28. The enclosure device as claimed in claim 27, wherein a diameter of the circular shape or a length of a longest side of the oval shape is 50-150 mm.

29. The enclosure device as claimed in claim 27, wherein a length of a shortest side of the oval shape is 20-100 mm.

30. The enclosure device as claimed in claim 16, wherein a height of the ring-shaped chamber is 1-50 mm.

31. An apparatus for use in the provision of pH control and stabilization to a bicarbonate based solution used in the in vitro dissolution testing of pharmaceutical products, comprising: a compartment which is configured to contain the bicarbonate solution, wherein the compartment is enclosed with an enclosure device as claimed in claim 16, and wherein the enclosure device is configured to partially isolate a gas environment in the compartment with that of the surrounding atmosphere.

32. A method of pH control and stabilization of a bicarbonate based solution used in the in vitro dissolution testing of pharmaceutical products, comprising: a) providing an apparatus comprising a compartment which is configured to contain the bicarbonate solution, wherein the compartment is enclosed with an enclosure device as claimed in claim 16, and wherein the enclosure device is configured to partially isolate a gas environment in the compartment with that of the surrounding atmosphere; b) introducing a bicarbonate solution into the compartment of the apparatus, wherein the bicarbonate solution does not fill the compartment, and a header space is present between the top of the bicarbonate solution and the top of the compartment; c) enclosing the top of the compartment with the enclosure device; d) connecting the enclosure device to a supply of a pH-decreasing gas; e) connecting the enclosure device to a supply of a pH-increasing gas; wherein, when a pH of the bicarbonate solution is to be decreased, pH-decreasing gas is supplied through the enclosure device into the header space above the bicarbonate solution such that a partial pressure of pH-decreasing gas on a surface of the bicarbonate solution increases such that the pH-decreasing gas dissolves into the bicarbonate solution which in turn decreases the pH of the bicarbonate solution; and wherein, when the pH of the bicarbonate solution is to be increased, pH-increasing gas is supplied through the enclosure device into the header space above the bicarbonate solution such that the partial pressure of pH-decreasing gas on the surface of the bicarbonate solution decreases such that the pH-decreasing gas escapes from the bicarbonate solution which in turn increases the pH of the bicarbonate solution.

33. The method as claimed in claim 32, wherein where the bicarbonate solution comprises bicarbonate ions as a primary or partial buffer specie with or without an addition of lipids and/or bile salts as would be found in a bio-relevant dissolution media.

34. The method as claimed in claim 32, wherein the gas environment of the compartment is isolated from that of the surrounding atmosphere while allowing leakage of gas into the atmosphere when a gas pressure within the container is higher than the atmosphere pressure.

35. The method as claimed in claim 32, wherein the pH-decreasing gas is pure carbon dioxide or carbon dioxide mixed with another gas.

36. The method as claimed in claim 35, wherein the carbon dioxide is mixed with is selected from oxygen and compressed air.

37. The method as claimed in claim 35, wherein, when the carbon dioxide is mixed with another gas, a concentration of carbon dioxide in the mixture is in the range of 1-99% and higher than that of the earth atmosphere, which is currently 0.04%.

38. The method as claimed in claim 32, wherein a pressure of the pH-decreasing gas supplied is 0.01-10 bar (1-1000 kpa).

39. The method as claimed in claim 32, wherein the pH-decreasing gas is supplied through the aperture on the base plate of the enclosure device, through the hollow cavity of the ring-shaped chamber and released out through the plurality of orifices at the bottom of the ring-shaped chamber into the header space.

40. The method as claimed in claim 32, wherein the pH-increasing gas is an inert gas.

41. The method as claimed in claim 40, wherein the inert gas is selected from argon, nitrogen and helium.

42. The method as claimed claim 32, wherein a pressure of the pH-increasing gas supplied is 0.01-10 bar (1-1000 kpa).

43. The method as claimed in claim 32, wherein the pH-increasing gas is supplied through the aperture on the base plate of the enclosure device, through the hollow cavity of the ring-shaped chamber and released out through the plurality of orifices at the bottom of the ring-shaped chamber into the header space.

44. The method as claimed in claim 32, wherein the pH level of the bicarbonate solution is measured using a pH electrode.

44. The method as claimed in claim 32, wherein the pH level of the bicarbonate solution is measured using a pH electrode.

45. The method as claimed in claim 44, wherein the pH level of the bicarbonate solution is continuously measured using the pH electrode.

46. The method as claimed in claim 32, wherein the pH control is achieved manually.

47. The method as claimed in claim 32, wherein the pH control is achieved automatically using a pH-controller and electric valves connected to the pH-increasing and decreasing gas supplies.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Other aspects and features of the present invention will become apparent to those ordinarily skilled in the art upon review of the following description of specific embodiments of the invention in conjunction with the accompanying figures.

[0033] FIG. 1 illustrates a bottom plan view of the lid portion of the enclosure device;

[0034] FIG. 2 illustrates a top plan view of the lid portion of the enclosure device;

[0035] FIG. 3 illustrates a side plan view of the lid portion enclosure device;

[0036] FIG. 4 illustrates a side cross-sectional view of the lid portion enclosure device;

[0037] FIG. 5 illustrates a bottom perspective view of the lid portion of the enclosure device;

[0038] FIG. 6 illustrates a top perspective view of the lid portion of the enclosure device;

[0039] FIG. 7 illustrates a top plan view of the ring-shaped chamber of the enclosure device;

[0040] FIG. 8 illustrates a bottom plan view of the ring-shaped chamber of the enclosure device;

[0041] FIG. 9 illustrates a side plan view of the ring-shaped chamber of the enclosure device;

[0042] FIG. 10 illustrates a side cross-sectional view of the ring-shaped chamber of the enclosure device;

[0043] FIG. 11 illustrates a top perspective view of the ring-shaped chamber of the enclosure device;

[0044] FIG. 12 illustrates a bottom perspective view of the ring-shaped chamber of the enclosure device;

[0045] FIG. 13 illustrates a side cross-sectional view of the assembled enclosure device;

[0046] FIG. 14 illustrates a top perspective view of the assembled enclosure device;

[0047] FIG. 15 illustrates a bottom perspective view of the assembled enclosure device;

[0048] FIG. 16 illustrates a side cross-sectional view of the enclosure device formed as a single unit;

[0049] FIG. 17 illustrates a top perspective view of the enclosure device formed as a single unit;

[0050] FIG. 18 illustrates a bottom perspective view of the enclosure device formed as a single unit;

[0051] FIG. 19 illustrates a schematic of an exemplary set up of the full apparatus;

[0052] FIG. 20 illustrates a graph illustrating maintaining pH 6.8 of bicarbonate buffer;

[0053] FIG. 21 illustrates a graph illustrating pH increase of bicarbonate buffer; and

[0054] FIG. 22 illustrates a graph illustrating pH decrease of bicarbonate buffer.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

[0055] FIGS. 1 to 15 illustrate an embodiment of the lid portion 11 and ring-shaped chamber 14 of enclosure device 10 of the present invention. The enclosure device 10 comprises a lid portion 11 which is attached to a ring-shaped chamber 14 which is completely or partially hollow inside 16. The lid portion 11 comprises a base plate 12 a spigot 13 and lip 15, the spigot 13 is configured to fit into the ring shaped chamber 14 and the lip 15 is configured to connect to the ring shaped chamber. In the alternative illustrated the lid portion and ring-shaped chamber are formed as separated components which are connected together, however, in the alternative they may be formed as a single component, which will obviate the need for the spigot 13 and lip 15 as illustrated in relation to the embodiment shown in FIGS. 16 to 18 discussed below. The base plate 12 has two apertures 18 that extend through the entire thickness of the base plate and through the entire thickness of the spigot 13. Each aperture 18 is configured to be connected to a supply of gas at one end thereof, this is achieved by connecting a tube 50 ideally made of metal (e.g. stainless steel or copper) into each of the apertures. The diameter of each of the apertures illustrated is 2.38 mm. Each of the tubes 50 is connected to a supply gas via a tube 52 typically formed from a plastics material which, when dissolved into the bicarbonate solution, will increase or decrease the pH. In an alternative where a single aperture is provided a t-junction may be provided which splits so that both the increasing and decreasing pH gas can be introduced using the same single aperture. The other end of the apertures 18 connect either directly or through a channel into the hollow cavity 16 in the ring-shaped chamber 14. At the bottom of the ring-shaped chamber (opposite to the base plate), a plurality of orifices 20 are made through the entire depth thereof. The distance between each of the orifices in the embodiment illustrated is about 13 mm. The diameter of each of the orifices in the embodiment illustrated is 1 mm. The angle at which each of the orifices passes through the bottom of the ring-shaped chamber is in the range of 45-90 in reference to the surface of the liquid (dissolution media) in the dissolution compartment. The orifices can be unidirectional (such as all in 90 angle in reference to the surface of the liquid) or in multiple-directions with mixed angles from 45-90 in reference to the surface of the liquid. In the embodiment illustrated the orifices are all at 90.

[0056] In one alternative of the invention (not illustrated), the chamber is attached to the base plate and the chamber is completely hollow inside. The gas is supplied through the aperture on the base plate directly into the hollowed cavity in the chamber. In another aspect of the invention (illustrated), the chamber is attached to the base plate and the chamber is partially hollow 16 inside. The gas is supplied through the apertures 18 on the base plate through a channel into the hollowed cavity 16 in the chamber.

[0057] The material of the base plate and the chamber is acrylic glass or any other inert and non-reactive material as known in the art.

[0058] The specific dimensions of the enclosure device 10 will depend on the type and size of the compartment or vessel that holds the bicarbonate solution. This means that the dimensions of the enclosure device 10 need to match that of the compartment or vessel 54. Such a compartment or vessel can be adapted from that are used in apparatus according to United States Pharmacopeia (USP) for dissolution testing of dosage forms, namely USP-I (rotating basket), USP-II (paddle), USP-III (reciprocating cylinder) and USP-IV (flow-through) apparatus. In addition to the apertures 18 on the base plate that are used for supplying the gas, other openings/gaps/holes 22, 24, 26 can be made in the plate. These include for example, an opening in the centre of the plate 22 for passing through the paddle/basket holder 58 according to the USP apparatus, an opening/hole 24 for inserting the pH electrode 60 into the dissolution medium, and openings 26 for taking/returning test samples from the bicarbonate solution via sample tubes 56.

[0059] FIGS. 16 to 18 illustrate an alternate embodiment of the present invention wherein the lid portion 111 and ring-shaped chamber 114 of enclosure device 110 are formed integrally rather than as separate components. FIG. 19 illustrates a schematic of an exemplary set up of the full apparatus. The full apparatus for which the enclosure device 10 of the present invention will be used includes a dissolution bath 62, in which a plurality of vessels 54 are located. Each vessel 54 that is in use is provided with an enclosure device 10 of the present invention (also called a vessel lid). Gas tubes 52 are connected to electric valves 66, which are in turn connected to gas regulators 64 which are in turn connected to gas cylinders 68. The pH meter 60 is connected to a pH monitor 70 to monitor the pH, which in turn is connected to a pH controller 72 such that when the pH monitor detects an increase or decrease in pH as required it will communicate the same to the pH controller, which in turn will communicate to the electric valves, which in turn will communicate with the gas regulators to introduce the required gas into the system. Sample tubes 56 are connected via a pump 74 to in this case a UV spectroscopy device 76 for analysing the contents of the vessel 54 and the whole apparatus can be controlled by PC 78. In one alternative the whole apparatus is controlled by a single PC 78, in an alternative the apparatus is controlled by two PCs 78, one controlling the pH and one controlling the dissolution, as illustrated.

Example 1: Method of Preparing Bicarbonate Buffer

[0060] Hydrochloric acid aqueous solution (0.1 M, Solution A) was heated to 37 C. in dissolution vessels used for USP I and II apparatus (Table 1). Sodium hydroxide aqueous solution (2M, Solution B) was added to solution A under stirring. Ions that comprise Hanks buffer were dissolved in water to desired concentrations (Solution C). One example of such composition is NaCI (73.3 mM/L), KCI (5.370 mM/L), Mg SO4.7H2O (0.812 mM/L), CaCl2 (1.260 mM/L), Na2HPO4.2H2O (0.337 mM/L) and KH2PO4 (0.441 mM/L). Solution C and D were added to the mixture of Solution A and B under stirring and adequate volume of deionised water was added to the vessel to make the final volume to 900 ml. The pH and buffer capacity of the resultant solution was measured using the InoLab pH720 meter after 1 minute of mixing at 50 rpm with the paddle apparatus (USP II).

TABLE-US-00001 TABLE 1 Components for preparing bicarbonate buffer Solution A Solution B Solution C Solution D 0.1M 2.0M Combination 0.2M HCl NaOH of ions NaHCO3 Water pH of Buffer capacity (ml) (ml) (ml) (ml) (ml) buffer (mMol/L/pH) 700 34 100 24 qs 900 5.6 1.7 700 34 100 32 qs 900 6.0 4.2 700 34 100 41 qs 900 6.2 7.1 700 34 100 63 qs 900 6.5 8.5 700 34 100 78 qs 900 6.8 10.9

Example 2: Method of Preparing Bicarbonate Buffer

[0061] Hydrochloric acid aqueous solution (0.1 M, Solution A) was heated to 37 C. in dissolution vessels used for USP I and II apparatus (Table 2). Sodium hydroxide aqueous solution (2M, Solution B) was added to solution A under stirring. Sodium bicarbonate powder was dissolved in Solution C (as described in Example 1) and the resultant solution was immediately added to the mixture of Solutions A and B. The pH of the resultant solution was measured using the InoLab pH720 meter after 1 minute of mixing at 50 rpm with the paddle apparatus (USP II).

TABLE-US-00002 TABLE 2 Components for preparing bicarbonate buffer Solution A Solution B Solution C Solution D 0.1M 2.0M Combination NaHCO3 HCl NaOH of ions as powder Water pH of Buffer capacity (ml) (ml) (ml) (g) (ml) buffer (mMol/L/pH) 700 33.2 100 0.54 qs 900 5.6 700 33.8 100 0.54 qs 900 6.0 700 34 100 0.54 qs 900 6.2 4.2 700 34.5 100 0.54 qs 900 6.5 4.9 700 34.9 100 0.54 qs 900 6.8 3.8

Example 3: Method of Preparing Bicarbonate Buffer

[0062] Hydrochloric acid aqueous solution (0.1 M, Solution A) was heated to 37 C. in dissolution vessels used for USP I and II apparatus (Table 3). Sodium hydroxide aqueous solution (2M, Solution B) was added to solution A under stirring. The FaSSIF/FeSSIF powder (for Solution E) (Biorelevant.com) was dissolved in Solution C (as described in Example 1). Sodium bicarbonate powder was dissolved in the above mixture of Solutions C and E. The resultant solution was immediately added to the mixture of Solutions A and B. The pH of the resultant solution was measured using the InoLab pH720 meter after 1 minute of mixing at 50 rpm with the paddle apparatus (USP II).

TABLE-US-00003 TABLE 3 Components for preparing bicarbonate buffer Solution Solution Solution Solution Solution D E Fasted or A B C NaHCO3 FaSSIF/ Fed status 0.1 M 2.0 M Combination in FeSSIF Target to be HCl NaOH of ions powder powder Water pH of simulated (ml) (ml) (ml) (g) (g) (ml) buffer Fed 700 34 100 0.54 11.2 qs 900 5.6 Fasted 700 33.2 100 0.54 2.24 qs 900 5.7

Example 4: pH Stabilisation at pH 6.8

[0063] Bicarbonate buffer of pH 6.8 was prepared using the method described in Example 2. The buffer was contained in dissolution vessels suitable for USP I and II. The vessel is enclosed using an enclosure device shown in FIGS. 1 to 15. Nitrogen (at a pressure of 4 bar (400 kpa)) and carbon dioxide (at a pressure of 0.1 bar (10 kpa)) was supplied to the vessel through the enclosure device. A Nico 2000 ELIT 6-channel pH control and monitoring system was connected to a 2-way solenoid valve to control the supply of the gases and to stabilise the pH of the solution at 6.8. FIG. 20 shows the pH changes of the solution within 60 minutes.

Example 5: pH Increase

[0064] Bicarbonate buffer solutions of pH 6.0-6.4 were prepared using the method described in Example 2. The buffers were contained in dissolution vessels suitable for USP I and II. The vessel is enclosed using an enclosure device shown in FIGS. 1 to 15 with holes either 45 or 90 degrees in reference to the surface of the solution. Nitrogen (at a pressure of 3 or 4 bar (300 or 400 kpa)) was supplied to the vessel through the enclosure device. FIG. 21 shows the pH increase of the solution within 30 minutes.

Example 6: pH Decrease

[0065] Bicarbonate buffer solutions of pH 7.5 were prepared using the method described in Example 2. The buffers were contained in dissolution vessels suitable for USP I and II. The vessel is enclosed using an enclosure device shown in FIGS. 1 to 15 with holes of 90 degrees in reference to the surface of the solution. Carbon dioxide (at a pressure of 0.1 bar (10 kpa)) was supplied to the vessel through the enclosure device. FIG. 22 shows the pH decrease of the solution within 15 minutes.

Example 7: Compatibility with Bio-Relevant Media

[0066] Bicarbonate buffer of pH 6.8 was prepared using the method described in Example 3, containing FeSSIF powder simulating the fed status. The buffer was contained in dissolution vessels suitable for USP I and II. The pH of the buffer was maintained at 6.8 using two methods.

[0067] Method 1: Nitrogen (at a pressure of 0.05 bar (5 kpa)) and carbon dioxide (at a pressure of 0.05 bar (5 kpa)) were purged directly into the buffer solution.

[0068] Method 2: The vessel is enclosed using an enclosure device shown in FIGS. 1 to 15. Nitrogen (at a pressure of 4 bar (400 kpa)) and carbon dioxide (at a pressure of 0.1 bar (10 kpa)) was supplied to the vessel through the enclosure device.

[0069] Results of pH Control:

[0070] Method 1: The purge of nitrogen or carbon dioxide caused bubbles in the solution. Immediately foaming was observed in the solution which spilt out the top of the dissolution vessel. The experiment could not be continued.

[0071] Method 2: No foaming or spillage was observed during the supply of the nitrogen and carbon dioxide gases. The pH of the bicarbonate solution was maintained at 6.80.5 for 60 minutes.