WO2004106281A1

WO2004106281A1 - Crystalline gabapentin

Info

Publication number: WO2004106281A1
Application number: PCT/IB2004/001776
Authority: WO
Inventors: Yatendra Kumar; Chandra Has Khanduri; Kiran Kumar Ganagakhedkar; Ruchika Chakraborty; Harish Niranjan Dorwal; Amit Rohatgi; Atulya Kumar Panda
Original assignee: Ranbaxy Laboratories Limited
Priority date: 2003-05-30
Filing date: 2004-05-28
Publication date: 2004-12-09

Abstract

The invention relates to a new crystalline polymorph of gabapentin and processes for producing the crystalline gabapentin. More particularly, it relates to the preparation of new crystalline form of gabapentin, referred to as 'Form IV' and pharmaceutical compositions that include the 'Form IV'. It also relates to a method of treatment of cerebral disorder comprising administration of the 'Form IV'.

Description

CRYSTALLINE GABAPENTIN

Field of the Invention

The field of the invention relates to a new crystalline polymorph of gabapentin and processes for producing the crystalline gabapentin. More particularly, it relates to the preparation of new crystalline form of gabapentin, referred to as 'Form IV' and pharmaceutical compositions that include the 'Form IN'. It also relates to a method of treatment of cerebral disorder comprising admimstration of the 'Form IN'.

Background of the Invetion

Chemically, gabapentin is l-(aminomethyl) cyclohexane acetic acid. U.S. Patent No. 4,024,175 discloses gabapentin, which is a synthetic amino acid related to γ-amino- butyric acid (GABA) and is used for treating convulsive type cerebral disorders, such as epilepsy, hypokinesia, including fainting and other cranial trauma. The process described in the patent gives non-hydrated gabapentin of a crystal structure identical to that of commercial or pharmaceutical grade gabapentin.

U.S. Patent No. 4,894,476 describes a monohydrate of gabapentin, which is formed by pouring a deionized water solution of gabapentin hydrochloride hydrate over an ion exchange column, eluting with deionized water, and concentrating the f actions to make slurry. An alcohol is then added to the slurry followed by filtration and drying to yield gabapentin monohydrate (1:1).

U.S. Patent No. 6,521,787 discloses another non hydrated polymorph of gabapentin referred to as Form II by the inventors, which is prepared by drying an aqueous solution of gabapentin using spray drying or turbo drying techniques. The Form II is characterized by its X-ray diffraction data.

U.S. Patent No. 6,255,526 discloses another crystalline Form III of gabapentin characterized by its specific powder X-ray diffraction pattern and IR spectrum. It is prepared by a process which involves reacting a solution of gabapentin hydrochloride with an amine to obtain gabapentin as a precipitate. A recent patent application, US 2003/92933 discloses two more anhydrous crystalline Forms A and B of gabapentin, which are prepared by dehydrating gabapentin monohydrate.

Summary of the Invention

hi one general aspect there is provided a crystalline polymorphic form of gabapentin, 'Form TV'.

The Form IV may have the X-ray diffraction pattern of Figure 1, infrared spectrum of Figure 2, and differential scanning calorimetry plot of Figure 3.

In another general aspect there is provided a pharmaceutical composition that includes a therapeutically acceptable amount of Form IN of gabapentin; and one or more pharmaceutically acceptable carriers, excipients or diluents.

In another general aspect there is provided a process for the preparation of Form IV of gabapentin. The process includes preparing a solution of gabapentin in one or more solvents; and recovering the gabapentin in the crystalline Form IV by the removal of the solvent.

The solvent may be one or more of lower alkanol, water or mixtures thereof. The lower alkanol may include one or more of primary, secondary and tertiary alcohol having from one to six carbon atoms. The lower alkanol may include one or more of methanol, ethanol, denatured spirit, n-propanol, isopropanol, n-butanol, isobutanol, and t-butanol. In particular, the lower alkanol may include one or more of methanol, ethanol, and denatured spirit.

Removing the solvent may include one or more of distillation, distillation under vacuum, evaporation, spray drying, freeze drying, filtration, filtration under vacuum, decantation and centrifugation.

The gabapentin in crystalline Form IV may be recovered from the solution by spray drying. The process may include further forming of the product so obtained into a finished dosage form.

The process may include further drying of the product obtained from the solution. The process may produce the crystalline Form IN of the gabapentin having the X- ray diffraction pattern of Figure 1, the infrared spectrum of Figure 2, and the differential scanning calorimetry plot of Figure3.

In another general aspect there is provided a method of treating or preventing cerebral disorder in a warm-blooded animal, the method comprising providing a pharmaceutical composition to the warm-blooded animal that includes Form IN of gabapentin.

The details of one or more embodiments of the inventions are set forth in the description below. Other features, objects and advantages of the inventions will be apparent from the description and claims.

Description of the Drawings

Figure 1 is X-ray diffraction pattern of gabapentin polymorphic form IV

Figure 2 is an infrared spectrum of gabapentin polymorphic form IN using potassium bromide pellets.

Figure 3 is differential scanning calorimetry plot of gabapentin polymorphic form

IN.

Detailed Description of the Invention

The inventors have found new crystalline form of gabapentin, referred to as 'Form IN'. The new crystalline form is characterized by its X-ray powder diffraction pattern as shown in Figure 1, infrared spectrum as shown in Figure 2 and differential scanning calorimetry plot as shown in Figure 3. The inventors also have developed a process for the preparation of the new crystalline form of gabapentin, by preparing a solution of gabapentin and recovering the gabapentin in the crystalline Form IN from the solution thereof in a suitable solvent. The inventors also have developed pharmaceutical composition that contain Form IN of the gabapentin, in admixture with one or more solid or liquid pharmaceutical diluents, carriers, and/or excipients.

In general, the solution of gabapentin may be obtained by dissolving gabapentin in a suitable solvent. Alternatively, such a solution may be obtained directly from a reaction in which gabapentin is formed. The solvent may be removed from the solution by a technique which includes, for example, distillation, distillation under vacuum, evaporation, spray drying, freeze drying, filtration, decantation, and centrifugation.

In one aspect, gabapentin in crystalline Form IN is recovered from the solution using a spray drying technique. A Mini-Spray Dryer (Model: Buchi 190, Switzerland) can be used. The Buchi 190 Mini-Spray Dryer operates on the principle of nozzle spraying in a parallel flow, i.e., the sprayed product and the drying gas flow in the same direction. The drying gas can be air or inert gases such as nitrogen, argon and carbon dioxide.

The term "suitable solvent" includes any solvent or solvent mixture in which gabapentin, is soluble, including, for example, lower alkanol, water and mixtures thereof. Examples of alkanol include those primary, secondary and tertiary alcohols having from one to six carbon atoms. Suitable lower alkanol solvents include methanol, ethanol, denatured spirit, n-propanol, isopropanol, n-butanol, isobutanol and t-butanol. Mixtures of all of these solvents are also contemplated.

If crystalline gabapentin is used as a starting material it may be in the form of any of the various polymorphic forms known in the prior art including solvates, hydrates, anliydrous or any other polymorphic forms of gabapentin. A solution of gabapentin obtained in situ during the preparation process may be used as such for spray drying.

The spray drying may be accomplished using a spray dryer which operates on the principle of nozzle spraying in a parallel flow, i.e., the sprayed product and the drying gas flow in the same direction. The drying gas can be air or one or more inert gases such as nitrogen, argon, and carbon dioxide. Moreover, the product obtained may be further or additionally dried to achieve the desired moisture values. For example, the product may be further or additionally dried in a tray drier, dried under vacuum and/or in a Fluid Bed Dryer.

It was found that lower outlet temperature to the spray drier results in a polymorphic form different from that disclosed in U.S. Patent No. 6,521,787 using spray- drying technique. Gabapentin may be prepared using the reactions and techniques known in the art including those described in U.S. Patent Nos. 4,024,175; 4,894,476; 6,255,526; 6,294,690; 5,095,148; and 5,149,870.

The concentration of the solution can be in the range from 2% to 11% by weight, for example from 5% to 7% by weight.

The air inlet temperature to the spray drier may range from 60 °C to 150 °C, or for example from 105 °C to 110°C and outlet temperature may range from 30 °C to 65 °C, or for example from 50 °C to 55 °C.

The pressure of nitrogen gas inlet may range from 5 to 10 bars, or for example 6 to 8 bars. Flow rate may be set in the range of 0.55 to 0.65 L/h, for example 0.6 L/h.

In general crystalline Form IN of gabapentin is characterized by X-ray peaks at about 6.12 and 17.00 ± 0.2 degrees two-theta. It may further contain peaks at 6.32, 16.22, 17.62, 18.00, 18.18 ± 0.2 degrees two-theta. Form IV of gabapentin may also be characterized by infrared spectrum in potassium bromide pellets as shown in Figure 2, and differential scanning calorimetry plot as shown in Figure 3.

Table 1 gives numerically the spacing "d" in A, 2 θ values and the relative intensity I (%) for the characteristic peaks of the X-ray diffraction spectrum of polymorphic form IV of gabapentin.

TABLE 1 - X-ray diffraction of the gabapentin Form IV polymorph

2 θ (degree) d-value (°A) I Io (%)

6.12 14.43 82

6.32 13.97 24

, 5 16.22 5.46 30

17.00 5.21 100

17.62 5.03 29

18.00 4.92 36

18.18 4.87 47

10 18.66 4.75 20

18.88 4.70 20

19.32 4.60 27

20.78 4.27 22

24.50 3.63 16

15 d = spacing in A

I/Io (%) = relative intensity

The resulting crystalline Form IN of gabapentin maybe formulated into ordinary dosage forms such as, for example, tablets, capsules, pills, solutions, etc. In these cases, the medicaments can be prepared by conventional methods with conventional 0 pharmaceutical excipients.

The compositions include dosage forms suitable for oral, buccal, rectal, and parenteral (including subcutaneous, intramuscular, and ophthalmic) admimsfration. The oral dosage forms may include solid dosage forms, like powder, tablets, capsules, suppositories, sachets, troches and lozenges as well as liquid suspensions, emulsions, pastes and elixirs. Parenteral dosage forms may include intravenous infusions, sterile solutions for intramuscular, subcutaneous or intravenous administration, dry powders to be reconstituted with sterile water for parenteral administration, and the like.

The gabapentin of crystalline Form IN can be administered for the treatment and prevention of convulsive type cerebral disorders, such as epilepsy, hypokinesia, fainting attacks and other brain trauma, in a warm-blooded animal.

For the purpose of this disclosure, a warm-blooded animal is a member of the animal kingdom possessed of a homeostatic mechanism and includes mammals and birds.

The present invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and are not intended to limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

Methods

X-Ray Powder Diffraction

X-ray powder diffraction patterns were recorded using the following instrument and parameters:

X-Ray Difractometer, Rigaku Coorperation,RU-H3R

Goniometer CΝ2155A3

X-Ray tube with Cu target anode

Divergence slits 1 0, Receiving slit 0.15mm, Scatter slit 1 0

Power:40 KN, 100 mA

Scanning speed: 2 deg/min step: 0.02 deg

Wave length: 1.5406 A

Infrared Spectra Infrared spectra were recorded using the following instrument and parameters: mstrument:Perkin Elmer, 16 PC

SCAN: lόscans, 4.0 cm^"1

According to the USP 25, general test methods page 1920, infrared absorption spectrum by potassium bromide pellet method.

Differential Scanning Calorimetry

Differential scanning calorimetry plots were recorded using the following instrument and parameters:

DSC821 e, Mettler Toledo

Sample weight: 3-5 mg

Temperature range: 25-100° C

Heating rate: 1° C/min

Nitrogen 80.0 mL/min

Number of holes in the crucible: 1

Preparation of gabapentin form IV

Example 1

Gabapentin (25g) was dissolved in 400 ml of distilled water at 25-30°C. Spray drier was set such as to have nitrogen gas inlet at 6-8 bars and flow rate was set at O.6L/T1.

Inlet temperature was kept between 106-110° C and outlet temperature was 51-54° C. Gabapentin was charged in the spray drier for 35 minutes and 10 g of white crystalline

Form IN of gabapentin was collected.

Moisture content: 0.09% w/w (by KF)

XRD, IR, and DSC spectra were similar to those shown in Figure 1, 2 and 3, respectively. Example 2

Gabapentin (15g) was dissolved in 300ml methanol at 40-42°C and cooled to 30- 35°C. The solution was subjected to spray drying with inlet temp at 90°C and the outlet temp at 65°C. The flow meter was set at 0.65 L/h and nitrogen supply at 6 bar. The solution was spray dried in 20minutes. The powder collected in the receiver was dried under vacuum for 12 hours at 40°C to yield 8g of the Form IN of gabapentin.

XRD, IR, and DSC spectra were similar to those shown in Figure 1, 2and 3, respectively.

Example 3

Gabapentin (28g) was dissolved in 380ml water. The solution was subjected to spray drying with inlet temp at 105 to 109°C and the outlet temp at 42 to 44°C. The nitrogen supply was set at 6 bar. The solution was spray dried in 20minutes. The powder collected in the receiver was dried under vacuum for 2 hours at 25 to 30°C to yield 18.5 g of the Form IV of gabapentin.

XRD, IR, and DSC spectra were similar to those shown in Figure 1, 2 and 3, respectively

While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present inventio

Claims

WE CLAIM:

1. 'Form IN' crystalline gabapentin.

2. The Form IN of claim 1 , wherein the gabapentin has the X-ray diffraction pattern of Figure 1.

3. The Form IV of claim 1 , wherein the gabapentin has the infrared spectrum of Figure 2.

4. The Form rV of claim 1 , wherein the gabapentin has the differential scanning calorimetry plot of Figure 3.

5. A crystalline Form IV of gabapentin characterized by X-ray diffraction pattern having peaks at about 6.12 and 17.00± 0.2 degrees two-theta.

6. The crystalline Form IV of claim 5, wherein the X-ray diffraction pattern is further characterized by peaks at about 6.32, 16.22, 17.62, 18.00, 18.18 ± 0.2 degrees two-theta.

7. A pharmaceutical composition comprising:

a therapeutically effective amount of Form TV gabapentin;

and one or more pharmaceutically acceptable carriers, excipients or diluents.

8. The pharmaceutical composition of claim 7, wherein the gabapentin has the X-ray diffraction pattern of Figure 1.

9. The pharmaceutical composition of claim 7, wherein the gabapentin has the infrared spectrum of Figure 2.

10. The pharmaceutical composition of claim 7, wherein the gabapentin has the differential scanning calorimetry plot of Figure 3.

11. A process for the preparation of crystalline Form IV of gabapentin, the process comprising:

preparing a solution of gabapentin in one or more solvents; and recovering the gabapentin in the crystalline Form IN from the solution thereof by the removal of the solvent.

12. The process of claim 11 , wherein the solvent comprises one or more of lower alkanol, water or mixtures thereof.

13. The process of claim 12, wherein the lower alkanol comprises one or more of primary, secondary and tertiary alcohol having from one to six carbon atoms.

14. The process of claim 13, wherein the lower alkanol comprises one or more of methanol, ethanol, denatured spirit, n-propanol, isopropanol, n-butanol,isobutanol, and t- butanol.

15. The process of claim 14, wherein the lower alkanol comprises one or more of methanol, ethanol, and denatured spirit.

16. The process of claim 11, wherein removing the solvent comprises one or more of distillation, distillation under vacuum, evaporation, spray drying, freeze drying, filtration, decantation, and centrifugation.

17. The process of claim 16, wherein the crystalline Form IV of gabapentin is recovered from the solution by spray drying.

18. The process of claim 16, wherein the spray drying is carried out in a spray drier using a drying gas.

19. The process of claim 18, wherein air inlet temperature to the spray drier ranges from about 60 °C to about 150 °C and outlet temperature ranges from about 30 °C to about 65 °C.

20. The process of claim 19, wherein the air inlet temperature to the spray drier ranges from about 105 °C to aboutl 10°C and outlet temperature ranges from about 50 °C to about 55°C.

21. The process of claim 18, wherein the drying gas is air or an inert gas.

22. The process of claim 21 , wherein the inert gas is nitrogen, argon or carbon dioxide.

23. The process of claim 18, wherein pressure of gas inlet ranges from 5 to 10 bars.

24. The process of claim 23, wherein the pressure of gas inlet is from 6 to 8 bars.

25. The process of claim 18, wherein flow rate of gas is in the range of 0.55 to 0.65 L/h.

26. The process of claim 25, wherein the flow rate is 0.60 L/h.

27. The process of claim 11 , wherein the solution of gabapentin has a concentration of from 2 % to 11 % by weight.

28. The process of claim 27, wherein the solution of gabapentin has a concentration of from 5 % to 7 % by weight.

29. The process of claim 11, further comprising additional drying of the product obtained.

30. The process of claim 11 , further comprising forming the product obtained into a finished dosage form.

31. The process of claim 11 , wherein the gabapentin has the X-ray diffraction pattern of Figure 1.

32. The process of claim 11 , wherein the gabapentin has the infrared spectrum of Figure 2.

33. The process of claim 11 , wherein the gabapentin has the differential scanning calorimetry plot of Figure 3.

34. A method of treating or preventing cerebral disorders in a warm-blooded animal comprising administering a pharmaceutical composition that includes a crystalline Form rv of gabapentin.

35. The method of claim 34, wherein the cerebral disorder is epilepsy, hypokinesia, including fainting, or cranial trauma.