KR20160007679A - Novel crystal form of doripenem - Google Patents

Abstract

The present invention relates to a doripenem crystal having a diffraction pattern of a powder X-ray diffraction having a characteristic peak at diffraction angles (2 theta) of 6.50, 11.32, 12.93, 15.35, 16.49, 17.52, 20.79, 23.12, 24.92 and 25.41 ± 0.2 (degrees). The present invention has a purpose of providing a novel crystal form of doripenem having excellent preservation stability, being easily handled, and having excellent solubility to water.

Description

NOVEL CRYSTAL FORM OF DORIPENEM < RTI ID = 0.0 >

The present invention relates to a novel crystalline form of doripenem and a method for producing the same.

Doripenem is a compound of formula (I) wherein the chemical name is (+) - (4R, 5S, 6S) -6 [(1R) -1-hydroxyethyl] -4- Yl] thio] -1-azabicyclo [3.3. ≪ RTI ID = 0.0 > 2. 0] hept-2-tin-2-carboxylic acid, which is a compound known to be useful in the application as an antimicrobial agent. These compounds have a broad spectrum of antimicrobial functions and are effective against both gram-positive and gram-negative bacteria.

Japanese Patent Application Laid-Open No. 5-294970 discloses an example in which the amorphous form of doripenem is separated. However, since the amorphous solid of doripenem has insufficient stability in storage, if it is stored for a long period of time under ordinary storage conditions, there is a problem that discoloration occurs and also the purity is lowered. Therefore, in order to develop doripenem as a medicament, it was necessary to formulate it into a crystalline form, which has better storage stability than an amorphous form.

Japanese Patent No. 2843444 discloses two types of crystals as a part of studies for improving storage stability and easy operability of doripenem. In the present specification, they are referred to as I type and II type, respectively. The I-type and II-type peaks have characteristic diffraction angles (2?) In X-ray diffraction as shown below:

Type I: 7.32, 14.72, 18.62, 20.42, 21.1, 22.18, 23.88, and 29.76 (degrees)

Type II: 6.06, 12.2, 14.56, 17.0, 18.38, 20.68, 24.38, 24.60, 25.88 and 30.12 (degrees)

However, in this field, we hoped that the stability of Doripenem would be further improved.

Thus, Korean Patent No. 0472842 proposes two new crystal forms of Doripenem. In the present specification, they are referred to as type III and type IV, respectively. The III-type and IV-type peaks have characteristic diffraction angles (2 [theta]) in X-ray diffraction as shown below.

Type III: 6.78, 6.96, 15.74, 17.92, 21.16, 23.56 and 25.80 (degrees)

IV: 13.04, 14.98, 15.88, 16.62, 20.62, 21.06, 22.18, 23.90, 26.08, 28.22 and 28.98

However, the types III and IV have insufficient solubility in water and are still insufficient to be used as medicines in the form of injections or powder filled preparations.

Patent Document 1: Japanese Patent Application Laid-Open No. 5-294970 Patent Document 2: Japanese Patent No. 2843444 Patent Document 3: Korean Patent No. 0472842

The first object of the present invention is to provide a crystalline form of novel doripenem which is excellent in storage stability, easy to handle, and excellent in solubility in water.

The second aspect of the present invention provides an antimicrobial composition which contains the doripenem crystal according to the first invention and is excellent in storage stability and solubility in water and can be suitably used as a medicine, especially an injection or powder filling agent .

A third aspect of the present invention is to provide a method for producing a doripenem crystal according to the first aspect of the present invention.

As a result of intensive investigations to solve the above problems, the present inventors have found that the characteristic peaks at diffraction angles (2θ) = 6.50, 11.32, 12.93, 15.35, 16.49, 17.52, 20.79, 23.12, 24.92 and 25.41 ± 0.2 Ray diffraction pattern showing excellent storage stability, easy handling, and high solubility in water, thereby leading to the completion of the present invention.

That is, the present invention solves the above problems by means of the following means:

(1) Dorypenem having a diffraction pattern of powder X-ray diffraction showing characteristic peaks at diffraction angles (2?) Of 6.50, 11.32, 12.93, 15.35, 16.49, 17.52, 20.79, 23.12, 24.92 and 25.41 ± 0.2 decision.

(2) Dorifenem crystals in which the doripenem is doripenem dihydrate.

(3) An antimicrobial composition containing the crystal.

(4) the composition is an injection.

(5) The antimicrobial composition wherein the composition is a powder filler.

(6) a step of dissolving (A) drippenem and an inorganic salt before processing in water, (B) precipitating crystals from the solution obtained by the step (A), and (C) And drying at atmospheric pressure.

7, wherein the inorganic salt is produced at least one selected from the group consisting of NaCl, KCl, MgCl _2, and CaCl _2.

(8) The method according to the above (8), wherein the inorganic salt is NaCl.

(9) The process according to any one of the above items (1) to (3), wherein the condition in the drying step of the step (C) is that the humidity is 30 to 100%, preferably 45 to 90%, more preferably 60 to 80% More preferably 20 to 30 ° C, and the drying time is 1 to 20 hours, preferably 2 to 15 hours, more preferably 3 to 10 hours.

The doripenem crystals of the first invention of the present invention have excellent storage stability, are easy to handle, and have high solubility in water.

The antibacterial composition of the second invention of the present invention is excellent in storage stability of Doripenem crystals as an active ingredient and has a high solubility in water, and can be suitably used as medicines such as injections or powders filled preparations.

According to the production method of the third invention, it is possible to easily produce the doripenem crystal of the first invention with excellent yield.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a diagram comparing crystal forms of samples of the initial, accelerated 1-month, and accelerated 3-month samples of the doripenem crystals of the first invention.
2 is a powder X-ray diffraction chart of the doripenem crystal of the first invention of the present invention.

(Doriphenem crystal)

The present inventor has found a new crystal form of doripenem through the measurement results in powder X-ray diffraction. In the present specification, this is also referred to as V-shape. The V-type crystal has the following characteristic peaks in powder X-ray diffraction.

Diffraction angles (2?) = 6.50, 11.32, 12.93, 15.35, 16.49, 17.52, 20.79, 23.12, 24.92 and 25.41

On the other hand, when the crystal structure is measured by X-ray diffraction, some measurement error may occur in the resultant value such as 2 &thetas; Specifically, a measurement error of about 0.2 (degrees) may occur at a value of 2?, And a measurement error of about 0.1 (degrees) at a value of 2? May occur even if a very precise equipment is used. Therefore, in the identification of each crystal structure, the measurement error must be taken into consideration.

However, even when the possible measurement errors are taken into account, characteristic peaks in the X-ray diffraction of the V-type crystal are completely different from the characteristic peaks in the X-ray diffraction of each of the I-type to IV-type crystals. That is, according to the X-ray diffraction method, the difference between the V-type crystal and the I-type to IV-crystal can be easily confirmed.

The moisture content of the V-type crystal is not necessarily constant, but may vary depending on drying conditions, storage conditions, and the like. In addition, the amount of the organic solvent remaining in the V-type crystal varies depending on the crystallization method or drying conditions, and is not constant.

In a preferred embodiment of the present invention, the V-form crystal is a hydrate. More preferably, the V-form crystal is a dihydrate.

These V-type crystals are more stable than I- and II-type crystals. The V-type crystal is similar in stability to the IV-type crystal, but has a higher solubility in water than the IV-type crystal. On the other hand, the III-type crystal disclosed in Patent Document 3 was produced by a known technique disclosed in the literature, but it was difficult to reproduce it, and further examination revealed that it was a mixed crystal, It was difficult to compare the physical properties of the resin.

(A composition containing doriphenem crystals)

The V-form crystals can be suitably used as a material for pharmaceutical preparations like other crystals of Forms I to IV. In particular, the V-type crystal can be used as an antimicrobial agent. When a composition containing V-form crystals as an active ingredient is used as an antimicrobial agent and administered to a subject in need thereof, oral administration or parenteral administration may be used. More specific dosage forms include injections (intravenous injection, intramuscular injection, ring gel, subcutaneous injectable ampoule, vial, liquid or suspension), external preparations, topical administration agents (such as eye drops, eye drops, eye drops, ointments, , A spray or suppository, etc.) or an oral administration agent.

Particularly, the injectable preparation can be prepared by dissolving the powder-filled preparation or the lyophilized preparation in physiological saline. At this time, if the solubility of the active ingredient of the injectable preparation in water is small, a precipitate is formed and the bioavailability is drastically reduced. However, since the V-type crystal has better solubility in water than known crystals, it is preferable to use the antibacterial composition of the present invention in the case of administering a drug containing doripenem as an effective ingredient in the form of an injection. It is more preferable than using a composition for antibacterial use.

(Preparation method of doriphenem crystals)

The V-type crystals can be prepared by precipitating crystals from a solution obtained by dissolving Crude doripenem and an inorganic salt in water or a mixed solvent of water and an organic solvent, and drying the crystals.

Crude doripenem can be synthesized by a conventionally known method. For example, the method disclosed in Patent Document 1 is possible.

When a mixed solvent of water and an organic solvent is used as a solvent in the dissolving step, alcohol, acetone, acetonitrile or tetrahydrofuran may be used as the organic solvent. As the alcohol, methanol, ethanol, isopropanol or isobutanol may be used. The mixing ratio of water and the organic solvent is preferably 1: 0.5 to 1: 100 (volume / volume).

In particular, it is preferable to use water as a solvent in the dissolution step.

The present invention is characterized in that an inorganic salt is dissolved together when the crude doripenem is dissolved in a solvent. The inorganic salt may be selected from the group consisting of NaCl, KCl, MgCl ₂ , and CaCl ₂ . In the present invention, the use of such an inorganic salt can reduce the amount of solvent, and further, there is an effect that a finally obtained crystalline form can be stably obtained. In addition, when such an inorganic salt is used, there is an advantage that even if only water, not an organic solvent, is used as a solvent, a desired crystal form can be obtained in the present invention.

The concentration of doripenem in the solution is preferably about 5 to 40% by weight, and the concentration of the inorganic salt is preferably 1 to 10% by weight.

The crystal of doripenem can be precipitated from the solution by appropriately using any crystallization operation such as cooling and / or stirring. Preferably, the solution is stirred while cooling the solution to about 0 to 10 DEG C to precipitate crystals of Doripenem.

As the drying method, a drying method under normal pressure and humidity conditions can be used. Specifically, the humidity is preferably 30 to 100%, more preferably 45 to 90%, and even more preferably 60 to 80%. The temperature is preferably 10 to 50 占 폚, more preferably 15 to 40 占 폚, and still more preferably 20 to 30 占 폚. The drying time is preferably 1 to 20 hours, more preferably 2 to 15 hours, and even more preferably 3 to 10 hours. If the drying conditions, especially the humidity conditions, are not satisfied, the crystal form finally obtained can be different from the originally intended crystal form.

Hereinafter, the present invention will be described by way of examples. It should be noted, however, that the following embodiments do not limit the scope of the present invention as an exemplary embodiment of the present invention, and various modifications may be made within the scope of the present invention.

[Example]

(Preparation and confirmation of V-shaped crystals)

After 200 ml of ion-exchanged water was heated to about 55 to 60 ° C, 4 g of NaCl and 20.0 g of Crude doripenem were added and dissolved therein. 1 g of activated carbon was added to this solution while maintaining at least 55 ° C Filtered through a filter. Thereafter, the filtrate was cooled to 0 to 10 ° C, and stirred for about 60 minutes to precipitate crystals. The crystals were further cooled to 0 to 5 ° C and aged for 2 hours to obtain crystals. The crystals thus obtained were washed with 40 ml of 50% isopropyl alcohol, dried at 20 to 25 ° C, at a humidity of 65 to 75% and at atmospheric pressure for 6 hours to obtain 16.3 g of a Dorifenem V crystal (Recovery rate 78.2%).

The results of analyzing the components and characteristics of the obtained crystals are as follows:

Elemental analysis criteria: For C ₁₅ H ₂₄ N ₄ O ₆ S ₂ .2H ₂ O

Theoretical values: C39.46, H6.18, N12.27, S14.05

Actual measurements: C39.53, H6.14, N12.40, S14.06

Moisture content

Theoretical value (dihydrate): 7.89%

Karl Fisher moisture meter (KF) measurement: 8.22%

Melting point: 168.4 占 폚 (decomposition)

The obtained crystals were tested according to USP X-ray diffraction under the following conditions:

<XRD measurement condition>

- Measuring range: 2.0 to 50.0 (degrees) (2?)

- Step Time: 5.9 seconds (2?)

- Step: 0.02 (degrees)

- Slit spacing: 0.6 mm

- Tube voltage and tube current: 40 kV and 40 mA

- CuKα line

The results of the powder X-ray measurement of the obtained crystals are shown in Fig. For the obtained crystals, the diffraction pattern of powder X-ray diffraction has characteristic peaks at diffraction angles (2?) = 6.50, 11.32, 12.93, 15.35, 16.49, 17.52, 20.79, 23.12, 24.92 and 25.41. Also, peaks at diffraction angles (2?) = 14.53, 27.99, 29.31 and 34.01 ± 0.2 (degrees) showed relatively low peaks.

As shown in Fig. 1, there was no change in crystal form in the obtained crystals at the initial stage, one month at acceleration and three months at acceleration.

(Evaluation of stability of V-type crystal)

The storage stability of the obtained crystals was evaluated at a temperature of 40 DEG C and a humidity of 75% to evaluate changes in the content, the amount of the substance in the initial stage, the accelerated one month and the accelerated 3 months,

Accelerated test results month content(%) Flexible Substance (%) ¹⁾ moisture(%) 0 (initial) 99.68 0.05 8.22 One 99.51 0.09 8.15 3 99.83 0.16 8.24

1) Doripenemic acid

As shown in Table 1, the V-form crystals produced less amount of the flexible substance over a long period of time and hardly absorbed moisture, so that the initial moisture content remained constant.

(Evaluation of solubility of V-type crystal)

The solubilities of the V-form crystals prepared by the above method and the IV-form crystals prepared by the method disclosed in Patent Document 3 were compared under the following conditions.

<Measurement Conditions>

- Reagent: water / ethanol

- Instrument: 15 mL conical tube / vortex mixer (Termo, Type 37600 Mixer)

- Test method: Weigh approximately 1 g of the crystals together with the reagents and measure the solubility at 30 ± 5 ° C for 30 minutes, shaking vigorously for 30 seconds.

The results are shown in Table 2.

Solubility comparison results reagent V-type crystal IV type crystal water record Record a little ethanol Does not melt Does not melt

As shown in Table 2, the V-type crystal was superior to the IV-type crystal in water solubility.

(Evaluation of drug efficacy of preparation using V-shaped crystals)

250 mg of the V-form crystal was dissolved in 100 mL of physiological saline to prepare an injectable solution, and the drug efficacy was evaluated. As a result, the same effect as the conventional type I and II crystals was obtained.

Claims (9)

Dorypenem crystals having a diffraction pattern of powder X-ray diffraction showing characteristic peaks at diffraction angles (2?) Of 6.50, 11.32, 12.93, 15.35, 16.49, 17.52, 20.79, 23.12, 24.92 and 25.41 (degrees). The doripenem crystal according to claim 1, wherein the doripenem crystal is a doripenem dihydrate crystal. An antimicrobial composition containing the crystal according to any one of claims 1 to 5. The antimicrobial composition according to claim 3, wherein the composition is an injection. The antimicrobial composition according to claim 3, wherein the composition is a powder filler. (A) a step of dissolving crude doripenem and an inorganic salt in water,
(B) precipitating crystals from the solution obtained by the step (A), and
(C) drying the crystals obtained by the step (B) under atmospheric pressure and humidity. The method according to claim 6, wherein the inorganic salt is at least one selected from the group consisting of NaCl, KCl, MgCl ₂ , and CaCl ₂ . 8. The process according to claim 7, wherein the inorganic salt is NaCl. 9. The method according to any one of claims 6 to 8, wherein the condition of the drying step (C) is that the humidity is 30 to 100%, the temperature is 10 to 50 占 폚, the drying time is 1 to 20 hours &Lt; / RTI &gt;

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