JPH0248547B2 - - Google Patents

Description

[Detailed description of the invention] The present invention relates to anticancer compositions.

The novel acid addition salts of the present invention possess the useful anticancer properties of the known free base compounds and have unexpectedly high water solubility, allowing them to be formulated into convenient clinical drug forms for intravenous administration. .

The acridine derivative m-AMSA [4'-(9-acridinylamino)methanesulfon-m-anisidide] has remarkable anticancer properties against animal cancer lines, according to Kane et al., Europ. J. Cancer 10, 539. −549 (1974)
has been reported. The compound has since been clinically evaluated with good initial results.

It is recognized that when anticancer agents such as m-AMSA are used clinically in humans, the solubility of the drug is often a controlling factor that determines the dosing method and drug form. For example, water-soluble drugs can generally be administered intravenously, whereas water-insoluble substances are limited to non-parenteral administration forms such as intramuscular and subcutaneous administration.
Water-soluble therapeutic agents can also be formulated into parenteral, non-oral or intravenous drug forms for administration to humans. It is therefore of critical advantage if the therapeutic fluid is water-soluble, especially when intravenous administration is likely to be the direct method of obtaining therapeutic blood concentrations of the drug in the human body.

The free base form of m-AMSA has very limited solubility in water and cannot be used as an intravenous drug form. Attempts have been made to produce acid addition salts to overcome this solubility problem, but the monohydrochloride and monomethane sulfonate salts are also reported to be clinically insufficiently water soluble. Current clinical formulations combine two sterilizing solutions before use. m in anhydrous N,N-dimethylacetamide in an ampoule.
- AMSA solution is added. Another bottle contains an aqueous L(+) lactic acid solution for dilution. The m-AMSM solution obtained by mixing these is administered by intravenous infusion.

This clinical preparation is in intravenous drug form, which has various drawbacks. Besides the obvious difficulties in drug form formulation and administration, it contains dimethylacetamide as an excipient. Dimethylacetamide has been reported to cause various toxic symptoms in animals, making it unsuitable or undesirable for use as a pharmaceutical excipient.

It is therefore an object of the present invention to provide a pharmaceutically acceptable, water-soluble, stable form of m-AMSA that can be administered intravenously (as well as by other means) and does not contain or require dimethylacetamide as a formulation excipient. It's about doing. This object as well as other features and advantages of the present invention will be readily apparent to those skilled in the art from the following specification.

The present invention relates to novel water-soluble acid addition salts of m-AMSA that can be reconstituted with sterile water or sterile aqueous vehicles for intravenous administration, and which are associated with previously known intravenous dosage forms of this drug. It does not have any disadvantages. In particular (1) about acetone per mole of lactate
(2) crystalline m- containing about 0.6 to 0.7 moles of acetone per mole of lactate;
AMSADL-monolactate acetone solvate; and (3) crystalline m-AMSAD(-)-monolactate hemiacetonate containing about 0.5 moles of acetone per mole of lactate.

FIG. 1 shows the infrared absorption spectrum of m-AMSA mono L(+)-lactate hemiacetonate pelleted in potassium bromide.

Figure 2 shows m-AMSA mono L(+)-lactate hemiacetonate in dimethyl sulfoxide.
Shows NMR spectrum (100MHz).

FIG. 3 shows the infrared absorption spectrum of the DL-monolactate acetone solvate of m-AMSA pelleted in potassium bromide.

Figure 4 shows the DL-monolactate acetone solvate of m-AMSA in dimethyl sulfoxide.
Shows NMR spectrum (100MHz).

Figure 5 shows the infrared absorption spectrum of D(-)-monolactate hemiacetonate of m-AMSA pelleted in potassium bromide.

Figure 6 shows the D(-)-monolactate hemiacetonate of m-AMSA in dimethylsulfoxide.
Shows NMR spectrum (100MHz).

Many common pharmaceutically acceptable acid addition salts of m-AMSA are very poorly soluble in water and are therefore not suitable for formulation into aqueous solutions for intravenous administration.
This is evident from the literature on hydrochloride and methanesulfonate salts and from solubility tests carried out by the inventors on salts such as sulfate, levulinate and citrate. In other words, the solubility of m-AMSA methanesulfonate in water is approximately 0.090 mg/
ml, and the solubility of m-AMSA hydrochloride, levulinate, and citrate in water is all lower than that of methanesulfonate, making it difficult to give accurate solubility values. be.

While studying the solubility of m-AMSA acid addition salts, Applicants discovered that the crystalline acetone solvated compounds of m-AMSAL(+)-monolactate, D(-)monolactate, and DL-monolactate were available for clinical use at room temperature. It was discovered that it has a sufficiently high water solubility to be used as an internal dosage form. These three crystalline salts also (1) have good stability both in solid form and when reconstituted with water;
(2) can be reconstituted with water to form a dilute solution of m-AMSA for intravenous administration (e.g. 3-5 mg/ml);
It remains clear (no salt precipitates) for at least several hours.

The crystalline lactate salts of the present invention are obtained by reacting m-AMSA base with L(+)-lactic acid, D(-)-lactic acid or DL-lactic acid in an acetone solvent. By stirring preferably at room temperature, the desired salt can be recovered from the solution by crystallization and filtration.

Before carrying out the above operation, m-
A solution of AMSA base and lactic acid may be obtained and filtered prior to mixing to form a crystalline composition. Lactic acid and m-AMSA base may be reacted in a ratio of about 1 to 4 molar equivalents of lactic acid per mole of m-AMSA. However, best results are obtained using an excess of lactic acid (at least 2 moles, most preferably about 2.5 moles). This reaction occurs over a wide temperature range, e.g. from about 0°C to
It can be carried out at temperatures up to 40°C, but is most conveniently carried out at room temperature. If necessary, seed crystals of the desired crystalline lactate salt can be added to the reaction mixture to effect crystallization and/or to enhance crystallization. After recovering the crystalline salt, wash it with acetone in the usual way, e.g. 16−24 at 50°C.
Dry occasionally using vacuum drying.

It has been found to be important to avoid contamination of chloride, sulfate, phosphate and carbonate ions in the starting materials and solvents in the production of monolactate salts. The presence of these ions causes (1) a decrease in the apparent initial solubility of the salt, (2) an increase in reconstitution times, and (3) precipitation of the salt from the aqueous solution upon standing.

Another aspect of the invention provides a stable water-soluble pharmaceutical solid dosage form for reconstitution with water or an aqueous vehicle as a stable solution of m-AMSA. The above drug forms are (1) crystalline L(+)-monolactate hemiacetonate containing about 0.5 mole of acetone per mole of lactate; crystalline m- containing about 0.6 to 0.7 mole of acetone per mole of lactate; AMSADL - Crystalline m-AMSAD containing about 0.5 moles of acetone per mole of monolactate acetone solvate or lactate
It is produced by the steps of (2) producing an aqueous solution of (-)-monolactate hemiacetonate and freeze-vacuum drying the produced aqueous solution.

Preparation of freeze-dried lactate acetonates is accomplished by simply adding an appropriate volume of crystalline L(+)-monolactate hemiacetonate, D(-)-monolactate hemiacetonate, or DL-monolactate acetone solvate. After dissolving it in water to make a complete solution, the aqueous solution (optionally after filtration) is subjected to a conventional freeze-vacuum drying process. Freeze-vacuum dried solid is m-AMSA
It has been found to contain about 1 mole of lactic acid per mole or no acetone. These can be easily reconstituted with water or aqueous vehicles to yield at least 3-5 mg/ml true solutions of m-AMSA with good stability.

The crystalline monolactate acetonate salts and lyophilized products produced by the present invention exhibit substantially the same anticancer properties as conventional m-AMSA forms. However, due to their high aqueous solubility they can be used to prepare single bottled and lyophilized clinical dosage forms for intravenous administration free of undesirable pharmaceutical excipients such as dimethylacetamide. All new drug forms are suitable for quick and convenient reconstitution with sterile water or sterile aqueous excipients. It has been discovered that a 3-5 mg/ml m-AMSA active aqueous solution of lactate acetonate salts or lyophilized product represents a particularly preferred drug form for intravenous administration.

The m-AMSA salts and lyophilized products of the present invention can be used to prepare oral or non-intravenous parenteral dosage forms and preferred intravenous injection products.

For the treatment of mammalian cancer, the dosage forms of the present invention can be administered either orally or parenterally, although parenterally is preferred in terms of administration and regimens previously published in the literature.

The following examples illustrate the invention:
This is not intended to limit the invention.

Example 1 Production of L(+)-monolactate hemiacetonate of m-AMSA 400 mg of m-AMSA was dissolved in 35 ml of acetone by stirring for 10 minutes. Add acetone while stirring this solution.
A solution of 450 mg (4 equivalents) of L(+)-lactic acid in 10 ml was added. A small amount of the resulting mixture was poured into a small glass tube with the tip of a glass rod to crystallize it. The crystals were added to the reaction mixture and stirred at room temperature for 2 hours. Excessively collect the formed orange crystals and wash with 10ml of acetone at 50°C.
0.53g of crystalline monolactate was vacuum dried at 18:00.
I got it.

Properties of mono L(+)lactate hemiacetonate: (a) Melting point: 135-143°C (decomposition) (b) Spectral analysis: IR, NMR and UV spectra in a solvent containing 0.5 mole of acetone per mole of m-AMSA It was consistent with the monolactate salt.

(c) H ₂ O%, (KF): 0.64 (d) Elemental analysis: C, 58.44; H, 5.58; N, 7.70;
S, 5.95.

(e) Solubility in water: 5 mg/ml.

(f) Stability: 15 ml of salt was redissolved in 10 ml of sterile water. The solution was stable for at least 24 hours and had less than 6% loss of activity after storage at 45°C for two weeks.

Example 2 Preparation of freeze-vacuum dried L(+)-monolactate hemiacetonate of m-AMSA 10 mg of crystalline m-AMSA monolactate hemiacetonate prepared according to Example 1 was added to 0.5 mg of m-AMSA monolactate hemiacetonate in an 8.2 ml flint bottle. ml sterile water. The bottles were lyophilized in a laboratory lyophilizer for 16 hours. Add 0.5 ml of sterile water to the bottle and shake for 2 minutes to obtain a solution.

This experiment was repeated by dissolving 10 mg of monolactate hemiacetonate in 15 ml of sterile water. Dilute solutions are preferred for freeze-vacuum dried product production.

Example 3 Sterile Crystallization of m-AMSA Mono L(+) Lactate Hemiacetonate 1 Slurry 1.0 g of m-AMSA free base in 100 ml of acetone at 22°C. A solution or something close to a solution can be obtained in 10 minutes.

2 Using aseptic techniques, pass the m-AMSA acetone solution through a sterile Millipore-Fluoropore or Miteix filter. Collect the liquid in a sterile glass or stainless steel container.

Wash the filter with 15ml of acetone and add the washing solution to the above solution. This is called solution A. Solution A
Use in step 5 within 5 hours.

3 Dissolve 1g of L(+) lactic acid in acetone and make the total amount 10
ml. (L(+) lactic acid 100 mg/ml) Stir for 5 minutes.

4. Using aseptic techniques, pass the acetone solution of L(+) lactic acid through a sterile Millipore-Fluoropore or Miteix filter. Collect the liquid in a sterile glass or stainless steel container. Add this to solution B
shall be. Do not wash the filter.

5 While gently stirring the whole solution A, 1-2
Add 5.8 ml of solution B over a period of minutes. This is L
Corresponds to 2.5 equivalents (0.58 g) of (+) lactic acid. Crystals must form within 10 minutes of stirring.

If no crystals form, sterile m-AMSA monolactate hemiacetonate seed crystals may be added or the interior surface of the container may be scraped with a sterile glass rod to induce crystallization.

6 Continue stirring for an additional hour after crystallization begins.

7. Strain the crystals through a lint-free sterilizer. Wash the crystals with 25 ml of acetone, previously passed through a sterile Millipore-Fluoropore or Miteix filter.

8. Vacuum dry the crystals at 50°C for 16 to 24 hours. m
The yield of -AMSA mono L(+)-lactate hemiacetonate salt is 1.1 g.

Example 4 Preparation of crystalline m-AMSA mono DL-lactate acetone solvate 150 mg of m-AMSA base in 15 ml of acetone at 45°C
The mixture was slurried for 15 minutes. A small amount of undissolved matter was removed by vacuum filtration through a 15 cm fine glass filter.
Add 0.15ml of 80% DL-lactic acid solution while rapidly stirring the solution.
added. Crystals formed within about 10 minutes. The mixture was then stirred for a further 30 minutes. The crystals were collected by vacuum filtration through a 15 cm fine glass filter. The crystals were washed with 2 ml of acetone and dried under vacuum at 50°C for 16 hours to obtain 180 mg of the title salt.

Properties: Elemental analysis: C, 59.05%; H, 5.55%;
H, 7.85%; S, 5.88% _H2O % (KF) = 1.03 Melting point: (capillary, uncorrected) 159-166°C (decomposed) NMR spectrum: Monolactate of m-AMSA with 0.6 mole acetone per mole of salt Agreed with salt.
The product is 20% in ACS purity DL-lactic acid as an impurity.
It contained about 0.1% lactyl lactate, which is produced by lactyl lactic acid present up to 0.1%. (This is DL-
Instead of lactic acid, equimolar amounts of pure L(+)-lactic acid and pure D
This can be avoided by using a (-)-lactic acid mixture. ) The resulting salt can be reconstituted with water to a 5-7.5 mg/ml solution. It remains clear for at least 6 hours at 17°C.

5, 7.5 and 10 mg/ml reconstituted aqueous solutions are 75〓
It was easily obtained by shaking for 3 minutes. The solubility of the salt in water at room temperature is at least 15 mg/ml.

Example 5 Preparation of crystalline m-AMSA mono DL-lactate acetone solvate 15 g of m-AMSA base was dissolved in 1.5 g of acetone at 22-24°C.
slurry for 10 minutes. The mixture was filtered under vacuum to separate the undissolved matter, which was washed with 50 ml of acetone. The solution and washing solution were combined into two Erlenmeyer flasks. To this was added 10.7 ml (2.5 equivalents) of 80% lactic acid solution over 1 minute. Crystal formation started 5 minutes after seed crystals of m-AMSADL-lactate acetone solvate were added to the reaction mixture. The mixture was stirred at 20-23°C for 1 hour. The mixture was vacuum filtered and washed with 150 ml of acetone. The washed crystals were vacuum dried at 50°C for 18 hours to yield 17.8g of the title product.
I got it.

Properties: NMR and IR spectra were consistent with those of the m-AMSA monolactate salt containing approximately 0.7 moles of solvated acetone per mole of salt. It also contained a small amount of lactyl lactate as an impurity.

Elemental analysis: C, 59.57%; H, 5.53%;
N, 7.84%; S, 5.81% H ₂ O% (KF) = 0.81 This salt could be easily reconstituted with sterile water to give a 7.5 mg/ml solution. The 5 and 7.5 mg/ml aqueous solutions remained clear at room temperature (17°C) for at least 16 hours.

Example 6 Preparation of Crystalline m-AMSA Mono DL-Lactate Acetone Solvent Compound 20 g of m-AMSA base was slurried in 2 parts of acetone at 25°C for 10 minutes. The mixture was vacuum filtered, undissolved matter was washed with 100 ml of acetone, and the washings were combined with the liquid. 11.45 ml (2.5 equivalents) of 85% DL-lactic acid was added to this solution for 1 minute with vigorous stirring, and crystals were formed within 5 minutes. The mixture was stirred for an additional hour, the crystals were collected by vacuum filtration, and acetone was added at 150 ml.
I washed it with ml. After drying the crystals under vacuum at 50° C. for 24 hours, 25 g of the title product was obtained.

Properties: Elemental analysis: C, 59.95%; H, 5.35%;
N, 7.61; S, 5.85%.

The IR and NMR spectra are m-containing approximately 0.67 moles of solvated acetone per mole of lactate salt.
It was consistent with that of AMSA monolactate salt. It also contained a small amount of lactyl lactate as an impurity.

Solubility test: Reconstituted aqueous solutions containing 7.5 and 10 mg of salt per ml of water remained clear for 24 hours at room temperature. The 15 mg/ml solution remained clear for 6 hours at room temperature.

Example 7 Freeze-vacuum drying of m-AMSA mono DL-lactate acetone solvate 180 mg of m-AMSA DL-lactate acetone solvate (prepared according to Example 6) was stirred and dissolved in 24 ml of sterile water. Transparent liquid (PH4.2)
was passed through a 1 inch 0.45 micron sterile Millipore filter. 2 ml of the solution was placed in a 7.2 cc flift bottle, and the solution was freeze-vacuum dried for 24 hours.

Add 2 ml of sterilized water to the freeze-vacuum dried bottle.
A 7.5 mg/ml clear solution was obtained. The solution remained clear at 17°C for at least 6 hours. The solution was shaken on a low speed horizontal shaker and remained a clear solution for up to 5 hours.

Example 8 Sterile Crystallization of m-AMSADL-Lactate Acetone Solvent Compound 1 1.0 g of m-AMSA base is slurried in 100 ml of acetone at 22-28°C. A solution or something close to a solution is obtained within 10 minutes.

2 Using aseptic techniques, pass the acetone solution through a sterile Millipore-Fluoropore or Miteix filter. Collect the liquid in a sterile glass or stainless steel container.

Wash the filter with 10ml of acetone and add the acetone solution to the solution. This is called liquid A. Solution A is used in step 5 within 5 hours.

3 Dissolve 1 g of DL-lactic acid (1.18 ml of 85% DL-lactic acid solution) in acetone to make 10 ml. (DL-lactic acid 100
mg/ml) stir for 5 minutes.

4 Using aseptic techniques, pass the acetone solution of DL-lactic acid through a sterile Millipore-Fluoropore or Miteix filter. Collect the liquid in a sterile glass or stainless steel container. This is called liquid B. Do not wash the filter.

5 While gently stirring all of the liquid A, add 5.8ml of liquid B.
Add for 1-2 minutes. This is 2.5 of DL-lactic acid.
equivalent weight (0.58g). If crystals do not form, sterile m-AMSADL-lactate acetone solvate seed crystals may be added or the interior surface of the container may be scraped with a sterile glass rod to induce crystallization.

6 After the start of crystallization, stir for an additional hour.

7. Collect the crystals in a lint-free sterilizer and wash with 10 ml of acetone, previously passed through a sterile Millipore-Fluoropore or Mytex filter.

8. Vacuum dry the crystals at 50°C for 16-24 hours. DL
- The expected yield of lactate acetone solvate is
It is 1.1g.

Properties: IR is as shown in Figure 3.

NMR is shown in Figure 4. It can be seen that up to 0.7 mol of acetone is a solvent in the salt. It also contains about 0.1 mole of lactyl lactate as an impurity.

Melting point: 159-166°C (decomposed) m-AMSA in salt: 72% (based on HPLC analysis) Water solubility: 25 mg/ml at room temperature Example 9 Dry-fil parenteral m-AMSADL-lactate acetone solvate compound Preparation method Prescription ^* Ingredients Per bottle Sterilized m-AMSADL lactate m-AMSA active acetone solvent compound. 0.02 g of 40-60 mesh ^** 1 Using aseptic technique, take the required amount of sterile 40-60 mesh of AMSA DL-lactate salt into a sterile bottle. Put on a sterile rubber stopper. Seal with aluminum seal. Place the bottle in a dark place and prepare for reconstitution.

2. To reconstitute, add enough sterile water for injection to make a 5 mg/ml m-AMSA active solution. The reconstituted solution can be stored at 20-25°C for 16 hours. Note: m-AMSA solutions are incompatible with chloride, sulfate and phosphate ions as they produce insoluble salts.

* Adding 100 mg of Mantonil has been shown to reduce reconstitution time with water.

**The amount of m-AMSADL-lactate acetone solvate compound is dependent on the potency of the salt, the required dose and the number of needle-syringe-bottle requirements. For example, if the product solution contains 0.7 moles of acetone per mole of salt, the m-AMSA content of this solution is 74.46
%. Therefore, 0.27 g of 100% pure m-AMSA DL-lactate acetone solvate is required to obtain 0.2 g of m-AMSA activity. This amount is then adjusted depending on the actual potency of the product, the required single dose, etc.

Example 10 Preparation of crystalline m-AMSAD(-)-monolactate hemiacetonate 1 1 g of m-AMSA base was dissolved in acetone at 22-28°C.
Make a slurry in 100ml. A solution or something close to a solution can be obtained within 10 minutes.

2 Using aseptic techniques, pass the m-AMSA acetone solution through a sterile Millipore-Fluoropore or Mitex filter. Collect the liquid in a sterile glass or stainless steel container.

Wash the filter with 10ml of acetone, filter the acetone solution through Millipore, and combine with the solution. This is called liquid A. Solution A is used in step 5 within 5 hours.

3 Dissolve D(-)-lactic acid in enough acetone to make 10 ml of acetone solution (100 mg/ml D(-)-lactic acid). Stir for 5 minutes.

4 Using aseptic technique, pass the acetone solution of D(-)-lactic acid through a sterile Millipore-Fluoropore or Miteix filter. Collect the liquid in a sterile glass or stainless steel container. This is called liquid B. Do not wash the filter.

5 While gently stirring all of the liquid A, add 5.8ml of liquid B.
Add over 1-2 minutes. This corresponds to 2.5 equivalents (0.58 g) of D(-) lactic acid. If crystals do not form, they will crystallize, so sterilization m-
AMSAD(-)-lactate acetone solvate seed crystals may be added or the inside surface of the container may be rubbed with a sterile glass rod.

6 After the start of crystallization, stir for an additional hour.

7. Collect the crystals in a suitable lint-free sterilizer. Wash the crystals with 10 ml of acetone, previously passed through a sterile Millipore-Fluoropore or Miteix filter.

8. Dry the crystals under high vacuum at 50°C for 16-24 hours. m
Typical yield of -AMSA D(-)-monolactate acetone solvate compound is 1.1 g.

Properties: IR is as shown in Figure 5.

NMR is as shown in FIG. Shows up to 0.4 mole of acetone solvated in salt.

Melting point: (capillary, uncorrected) 180-184°C. (Decomposition) m-AMSA in salt: 78.4% (based on HPLC analysis) Elemental analysis: C, 59.47%; H, 5.20%;
N, 8.41%; S, 6.46%.

H ₂ O% (KF): 0.39 Example 11 Freeze-vacuum drying of m-AMSA D(-)-monolactate acetonate The m-AMSA DL-lactate acetone solvate in the method of Example 7 was dissolved in an equimolar amount. Example
If the method of Example 7 is repeated with the m-AMSAD(-)-monolactate acetone solvate prepared in step 10, when reconstituted with water, at least 3
-5mg/mlm- A freeze-vacuum dried solid that becomes an AMSA active solution can be produced. This solid contains no acetone, which was analyzed to be 1 mole of m-AMSA per mole of D(-)-lactic acid.

[Brief explanation of drawings]

FIG. 1 is an infrared absorption spectrum diagram of the m-AMSA mono L(+)-lactate hemiacetonate of the present invention formed into pellets in potassium bromide. The vertical axis shows transmittance (%), and the horizontal axis shows wave number (cm
^-1 ) and wavelength (microns). Figure 2 shows the composition of m-AMSA mono L(+)-lactate hemiacetonate of the present invention in dimethyl sulfoxide.
It is an NMR spectrum diagram (100MHz). on the horizontal axis
Shows ppm. Figure 3 shows the m-AMSA of the present invention.
FIG. 2 is an infrared absorption spectrum diagram when a DL-monolactate acetone solvent compound is made into a pellet in potassium bromide. The vertical axis shows transmittance (%), and the horizontal axis shows wave number (cm ^-1 ) and wavelength (microns). FIG. 4 is an NMR spectrum (100 MHz) of the m-AMSA DL-monolactate acetone solvent compound of the present invention in dimethylsulfoxide.
The horizontal axis shows ppm. Figure 5 shows the m-
FIG. 2 is an infrared absorption spectrum diagram of AMSA D(-)-monolactate hemiacetonate pelleted in potassium bromide. Transmittance (%) on vertical axis
, and the wave number (cm ^-1 ) and wavelength (microns) are plotted on the horizontal axis.
It shows. Figure 6 shows m-AMSA D of the present invention.
It is an NMR spectrum diagram (100MHz) of (-)-monolactate hemiacetonate in dimethylsulfoxide. The horizontal axis shows ppm.

Claims (1)

[Claims] 1. Crystalline monolactate acetonate of 4'-(9-acridinylamino)methanesulfon-m-anisidide. 2. The compound according to claim 1, which is crystalline mono-L(+)-lactate hemiacetonate of 24'-(9-acridinylamino)methanesulfon-m-anisidide. 3 Crystalline monomer of 4'-(9-acridinylamino)methanesulfon-m-anisidide containing 0.6 to 0.7 mol of acetone per mol of lactate salt
The compound according to claim 1, which is a DL-lactate acetone solvate. 4. The compound according to claim 1, which is crystalline mono-D(-)-lactate hemiacetonate of 4'-(9-acridinylamino)methanesulfon-m-anisidide. 5 (1) 4'-(9-acridinylamino) of lactic acid
producing a solution of 4'-(9-acridinylamino)methanesulfon-m-anisidide and acetone lactic acid in a molar ratio of 1:1 to 4:1 to methanesulfon-m-anisidide; (2) From the above solution, 4'-(9-acridinylamino)
4′-(9-
acridinylamino)methanesulfone-m-
A method for preparing a crystalline monolactate acetonate solvate compound of anisidide. 6. A process according to claim 5, wherein from 2 to 2.5 moles of lactic acid are used per mole of 4'-(9-acridinylamino)methanesulfone-m-anisidide. 7. The method according to claim 5, wherein step (1) is carried out at a temperature of 0 to 40°C. 8. The method of claim 5, wherein the solution produced in step (1) is substantially free of chloride, sulfate, phosphate or carbonate ion contamination.