CA1159369A - Crystalline mono dl-lactate hemiacetonate of 4-(9- acridinylamino) methanesulfo-m-anisidide - Google Patents

Abstract

Abstract This invention concerns three particular crystalline monolactate salts of the antitumor agent 4'-(9-acridinylamino)methanesulfon-m-anisidide. The salts are characterized in having unexpectedly high water-solubility.

Description

3`~3 Back~_ound of the Invention 1. Field of.the Invention __ The novel acid addition salts of th~ present invention possess the advantageous antitumor properties of the known free base compound and in addition have unex-pectedly high water-solubility, thus allowing preparation of useful clinical dosage forms ~or intravenous adminis-tration.

2. Description of the Prior Art The acridine derivative m-AMSA [4'-(9-2cridinyl ami~o)methanesulfon-m-anisidide~ was reported by Cain, et al_ in Eu~ . J._Cancer 10:539-549 (1974) to possess significant antitumor activity in animal twnor systems.
Since ~hen, this compound has been subjected to clinical evaluation with very promising initial results.
When an antitumor agent such as m-AMSA is em-ployed for h~man clinical use, it is recognized that solu-bility of the agent i5 often the cont~olling factor in determining route of administration and dosage forms. :For insta~ce, a water-soluble substance can be generalLy ad-ministered intravenously whereas a water-insoluble mate:rial is limited to other forms of paren~eral administration such as intramuscular and subcutaneous. A therapeutic agent having water-~solubility also faciliates preparation of oral and non-intravenou~ parenteral dosage forms for human ad-mlnistration. Thus, it is decidedly advan~ageous i.~ a therapeutic agent is water-soluble, particularly when one considers that -the most direct route ~or achieving thera-peutic blood levels o~ a drug within the human body is by intravenQus administration.
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9 The free base form o~ m-AMSA has very limited solubility in water and thus cannot be used as a dosage form for intravenous administxation. Attempts have been made to prepare acid addition salts to overcome this solubility problem, but ~he reported monohydrochloride and monomethane-sulfonate salts also proved insufficiently water-soluble for clinical use. The formulation presently in clinical use consists of two sterile liquids combined prior to use. A
solution of m-AMS~ in anhydrous N,N-dimethylaceta~mide is contained in an ampule. A separate vial contains an aqueous L(~) lactic acid solution for use as a diluen~. When mixed the resulting m-AMSA solutio~ is administered by i.v. infusion.
While the present clinical formulation provides an i~travenous dosage form, it suffers from several disad~antages.
In addition to the obvious difficulties in preparing and administering the dosage form, it contains dimethylacetamide as a vehicle. Dimethylacetamide has been reported to show various toxic symptoms in animals and may thus prove to be unacceptable or undesirable as a pharmaceuticaL vehicle.
It is accordin~ly an object of the present in-vention to provide a water-soluble, stable, therapeutically acceptable form o~ m-AMSA which can ~e administered intra-venouæly (a~ weLl as by other routes) and which does not con-tain or require dimethylacetamide as a ph~rmaceutlcal vehicle.
This object as well as other features and advantages of the invention will be readily apparent to those skilled in the art from the disclosure set out below.

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rrhe present invention provldes novel water-soluble acid addition salts oE m-AMSA which upon recon-stitution with sterile water or a sterile aqueous vehicle can be administered intravenously and which do not have the disadvantages associated with the known intravenous ~orms o~ this agent.

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Mo~e particularly, there are provided (1) the crystalline L(+)-monolactate hemiacetonate of m-AMSA contalning about O.5 moles of acetone per mole of lactate salt, (2) the crystalline m-AMSA DL-monolactate acetone solvate containing from about 0.6 to 0.7 moles of acetone per mole of lactate salt and

(3) ~he crystalline m-AMSA D(-)-monolactate hemiacetonate containing about 0.5 moles of acetone per mole of lactate sàlt.
Description of the Drawings IG. L shows the infrared absorption spectrum of m-AMSA
mono L(~)-lactate hemiacetonate when pelleted in potasssium bromide. IG. 2 shows the NMR spectrum o~ m-AMSA mono L(+)-lactate hemiacetonate in dimethylsulfoxide (100 MHz). IG. 3 shows the infrared absorption spectrum of the DL-monolactate acetone solvate of m-AMSA when pelleted in potassium bromide. IG. 4 shows the ~MR spectrum of the DL-monolac~ate acetone solvate of m-AMSA in dimethylsulfoxide (100 ME~Z). IG~ S shows the infrared absorption spectrum of the D(-)-monolactate hemiacetonate of m-AMSA when pelleted in potassium bromide. I~. 6 shows the NMR spectrum of the D(-)-monolactate hemiacetonate of m-AMSA in dimethylsulfoxide (100 MHz).

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~ any conve~tional pharmaceutically acceptable acid addition salts of m-AMSA are onLy ~lightly soluble in water and are thus unsuited for preparation o~ aqueous intra~enous solu-3~

-4-tions. This is evident from literature references to thehydrochloride and methanesulfonate salts as well as from solubility tests carried out by the present inventors on salts such as the sulfate, levulinate and citrate.
In investigating solubility properties o~ m-AMSA
acid addition salts, we have unexpectedly found that the crystalline acetone solva~es of m-AMS~ L(+)-monolactate, D(-)-monolactate and DL-monolactate possess sufficiently high water-solubility at room temperature to provide acceptable intravenous dosage forms for clinical use.
Additionally, these three crystalline salts (1) have ex~
cellent stability both in solid form and upon.reconstitution with wa~er and (2) can be reconstituted with water to form dilute solutions (e g. 3 5 mg/ml) of m-AMSA for intravenous administration which remain clear (no precipitation of salt) for at least several hours.
Preparation of the crystalline lactate salts of the present invention is accomplished by reacting m-AMSA
base with L(~)-lactic acid, D(-)-lactic acid or DL-lactic acid in an acetone solvent. Upon stirring, preferably at room temperature, the desired salt crystallizes ~rom solution and may be recovered as by filtration.
It is pre~erred in carrying out the above prc~cess to firs~ obtain the m-AMSA base and lactic acid in acetone solution and then ~ilter them before mixing to foxm the crystalline product. The lactic acid and m-AMSA base may be reacted in proportions o~ about one to four molar equi-valents of lactic acid per mole of m~SA. For best results, however, an excess o.f lactic acid (p~e~erably at least two and most pre~erably about 2.5 molar equivalents) is employed~
The reactio~ may be carriecl out over a wide temperature range, e.g. ~rom about O~C. to 40C., but i3 most advan-tageously conducted at room temperature. IE clesired seed crystals o~ the desired crystalline lactate salt may be 3~

added to the reaction mixture to induce and/or enhance crystallization. After recovery the crystalline salt is washed with acetone and dried by conventional procedures, e.g. vacuum-drying at 50C. for 16-24 hours.
We have found that it is important in preparing the monolacta~e salts to avoid contaminating ions of chloride, sulfate, phosphate and carbonate in the starting materials and solvent. The presence of such ions can possibly result in (1~ a reduction over time in the apparent initial solu-bility of the salt, (2) an increase in reconstitution t:ime and (3) precipitation o the salt from aqueous solution upon standing.
Accordin~ to another aspect of the presen~ invention, ~here is provided a stable~ solid, water-soluble pharmaceutical dosage form for reconstitution with water or aqueous vehicle as a stable solution of m-AMSA, said dosage form being pro-duced by the steps o~
(1) forming an aqueous solution of crystalline L(~)-monolactate hemiacetonate of m-A~SA containing about 0.5 moles of acetone per mole of lactate salt, crystalline m-AMSA DL-monolactate acetone solvate containing from abou~ 0.6 to 0.7 moles of acetone per mole of lactate salt or crystalline m-AMSA
D(-)-monolactate hemiacetonate containing about 0.5 moles of acetone per mole of lactate salt;
and (2) lyophilizing the so-produced aqueous solution.
Preparation of the lyophilized lactate acetonates i~ accompliihed by simply di~solving the crystalline L(~
monolactate hemiace~onate, D(-) monolactate. nemiacetonate or DL monolactate acetone solvate in a suitable volume o.~ water ko Eorm a complete ~olution and then subjecting the aqueous solution (a~ter arl optional filtration step) to a conventional lyophilization procedure. The lyophilized ~olids are found to contain abou~ one mole o~ lac~ic acid per mole of m-AM5A
and to be free of acetone. They can be easiLy r2constituted wi~h water or aqueous vehicle -to give at leas~ 3-5 mg/ml true solutions of m-AMSA having excellent stability charac-teristics.
The crystalline monolacta~e ace.tonate salts and lyophilized products provided by the present invention ex-hiblt substantially the same antitumor properties as the prior art m-AMS~ ~orms. 8ecause of their high water-solubility, however, they may be used to prepare single vial dry-fill and lyophilized clinical dosage forms for intravenous administra~ion which do not contai~ an undesirable pharmaceutical vehicle such as dimethylacetamide. The new dosage forms are all suitable for rapid and convenient recons~itution with sterile wa~er or a sterile aqueous vehicle. We have found tha~ a 3-5 mg/ml m-A~SA activity aqueous solution of the lactate acetonate salts or lyophilized produc~s provides a particularly pre-ferred dosage form for intravenous administration.
The m-AMSA salts and lyophilized products o~ the present in~ention may be used to prepare oral or non-intravenous parenteral dosage forms as well as the preferred intravenous injectable product.
In the treatment of mammalian tumors, the dosage forms of the present inventlon may be administexed either orally or parenterally but preferably parenterally, in dosages and according to regimens previously disclosed in the litera-ture.
The ~ollowing examples are given in illustration of, buk not in limi-tation of, the present invention.

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Preparation of L(+)-Monolactate Hemiace~onate of m-~M5A
m-~SA (400 m~) was dissolved in 35 ml of acetone after 10 minutes of stirring. To ~his solution ~here was added with stirring a solution of 450 mg (4 equivalents) of L(~) lactic acid in 10 ml of acetone. An aliquot of the re sulti~g mix~lre was glass rod-scratched in a small glass test t~be to form crystals. The crystals were added to the r~action mi~ture and the mixture was stirred for 2 hours at room temperature. The orange crystals which fo~med wexe re-moved ~y filtration, washed wi~h 10 ml of acetone and ~acuum-dried at 50C. for 18 hours_ Yield of crystalline mono-lactate: 0.53 grams.

Properties of mono L(+) lactate hemiace~onate-~a) MeltL~ polnt: 135-143C. (decomposition) ~b) Spectral analysis: IR, NMR and W spectra were con~istent for a solvated monalactate salt containing 0.5 mole acetone per mole o~ m-ANSA
~c) % ~0, ~F = 0.64 td) Elemental Analysis: C, 58.44; ~, 5.S8;
N, ~.70; S, 5.95~
(e) Salubility in water: 5 mg/ml.
(f) Stabili~y: 15 mg salt was reconstituted w:ith 10 ml sterile water, The solution was stable ~or at least 24 hour~ and showed le~ than a 5% activity loss a~ter 2 weeks' storage a~ 45aC.
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Pre~aration o~ L~oDhlli~ed L(~--onolactate ~Iemiacetonat~
0~ MS~
The cry~talline m-AMSA ~onolactate hemiacetonate (10 mg) prepared according to Example 1 was dissolved in 3~ 3 0.5 ml sterile wa~er in an 8.2 ml flint vial. The vial was lyophllized on a laboratory lyophilizer for 16 hours.
Sterile water (0.5 ml) was added to the vial. A solution was obtained after two minutes of shaking.
This experiment was repeated using 10 mg of the monolactate hemiacetonate salt dissolved in 15 ml of sterile water. The more dilute solu~ion is preferred for preparing lyophilized product.
Ex ~ple 3 _terile Crystall_~t on ~ s~ Mono L(+) Lactate Hemiacetonate i. Slurry 1.0 g of m-~A free base in 100 ml of acetone at 22-28C~ A solution or near solution is ob-tained in 10 minutes.
2. Using aseptic techniquel pass the acetone solutio~ of m-AMSA through a sterile Millipore-Fluoropose or Mitex filter. Collect the filtrate in a sterile glass or stainless steel container, Wash the filter with 15 ml of acetone and add the filtered acetone to the above filtrate. This is Solution Aq Use solu~ion A in Step 5 within 5 hours.
3. Dissolve one grant of L(+) lactic acid; q.s.
to 10 ml. in acetone (100 mg/ml of L(+) lactic acid). Stir f or 5 minutes .
4. Using aseptic technique pass the acetone solution of L~+) lactic acid through a sterile Millipore-Fluoropore or Mitex filter, Collect the filtrate in a s terile gla5~ or stainless s~eel container. This is Solution B, Do not wash the filter.
S. With moderate stirriltg add 5.8 ml of Solution B to all o~E Solution A over a 1~2 millute interval. This repre~ent~ ~.5 equivalents (0.58 g) o~ L(~) lactic acid.
Crystal~ should ~orm in 10 minutes o~ stirrin~.

~: , If crystals do not ~orm, sterile m-AMSA
monolactate hemiacetonate seed crystals may be added or the sides of the container may be scratched with a sterile glass rod to induce crystallization, 6. Stir an additional l hour after onset of crystallization.
7. Remove the crystals by lint--free sterile filtration technique. Wash the crystals with 25 ml of acetone previously filtered through a sterile Millipore~
Fluoropore~or Mitex~filter, 8. Va~uum-dry the crystals at 50C, for 16-24 hours. Yield of m-AMSA mono L(+) lactate hemiacetonate salt is l.l g.
Example 4 Preparation of Cr~stalline m-AMSA Mono DL-Lactate Acetone Solvate m-AMSA base (150 mg) was slurried in 15 ml of acetone for 15 minutes at 45C. A small amount of in-solubles were removed by vacuum filtration through a 15 cm fine glass filter. To the filtrate there was added 0.15 ml of an 80~ DL-lactic acid solution with rapid stirring. Crystals Eormed in about 10 minutes. The mix-ture was then stirred an additional 30 minutes. The crystals were removed by vacuum filtration through a 15 cm fine gla~s f ilter. The crystals were ~hen washed with 2 ml of acetone and vacuum-dried at 50C for 16 hours. There was obtained 180 mg of the title salt.
Elemental analysis: C, 59.05~; H, 5.55~, H, 7.85%; S, 5.88 ~ ~12O(KF) ~ 1.08.
m.p. (capillary, uncorrected) ~ 159-166C
(decomposltion).
NM~ spectrum of the product was consistent for a monolactate salt of m-AMSA containing 0.6 t mole of acetone per mole of salt. The product contained as an impurity approximately 0.1 mole % of lactyl lactate salt which is formed due to the presence of up to 20~ of lactyl lactic acid in ACS purity DL--lactic acid.*
The product salt may be reconstituted with water to give a 5-7.5 mg/ml solution which remains clear at 17C for at Least 6 hours.
Reconstituted aqueous solutions of 5, 7.5 and 10 mg/ml were readily obtained with 3 minutes shaking at 75F. Solubility of the salt in water at room temperature is at least 15 mg/ml.
*This may be avoided by using in place of the DL-lactic acid an equimolar mixtuxe of pure L(+)-lactic acid and pure D(-)-lactic acid.

Example 5 Preparation of Crystalline m~AMSA Mono DL-Lactate_Acetone Solvate m-AMSA base (15 g) was slurried in 1.5 liters of acetone at 22-24C for 10 minutes. The mixture was vacuum-filtered and the insolubles were washed with 50 ml of acetone. The wash was added to the filtrate and the filtrate then placed in a 2 liter Erlenmeyer flask. There was added over a one minute interval 10.7 ml of an 80% DL-lactic acid solution (2.5 equivalents). The reaction mixture was seeded with crystals of m-AMSA DL-Lactate acetone solvate.
Crystals began to ~orm in 5 rninutes. The mixture was stirred ~or L hour at 20~23C. Crystals were removed by vacuum-~ tration and washed with lS0 ml aoetone. The washed crystals were vacuum-dried a-t 50C for 13 hours to give 17.8 g o~ title product~

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Properties: NMR and IR spectra were consistent for a monolactate salt of m-AMSA having approximately 0.7 mole of solvated acetone per mole of salt.
Also present were small amounts of lactyl lactate as an impurity.
Elemental analysis: C, 59.57%; H, 5~53%;
N, 7.84%; S, 5.81~.
~H2OtKF) = 0.81.
The salt could be readily reconstituted with sterile water to form a 7.5 mg/ml solution.
Aqueous solutions having concentrations of

5 and 7.5 mg/ml xemained clear for at least 16 hours at room temperature (17C).

Example 6 Preparation of Crystalline m-AMSA Mono DL-Lactate Acetone .. .. _ . , _ _ _ . . . _ Solvate m-AMSA ba~e (20 g) was slurried in 2 liters of acetone at 25C for 10 minutes. The mixture was vacuum-filtered and the insolubles were washed with 100 ml acetone (the wash was then added to the filtra-te). There was added to the filtrate with rapid stirring over a 1 minute interval 11.45 ml o~ 85~ DL-lactic acid (2.5 equivalents). Crystals formed in ~ive minutes. The mixture was stirred an additional one hour. Crystals wer~ removed by vacuum-filtra-tion and washed with lSQ ml o~ acetone. Upon vacuum-drying the crystals at 50C ~or 24 hours, there was ob-tained 25 grams o~ the title product.
ropert _ : Elernental Analysis: C, 59.95~; H, 5.35~;
N, 7.61~; S, 5.85~.
IR and NMR spectra were consistell-t Eor a monolactate salt o~ m-AMSA having approximately 33~)~

0.67 mole o~ solvated aceto~e per mole of lactate salt. Also present were small amounts of lactyl lactate a.s an impurity.
Solubility testing: Reconst:ituted aqueous solutions of 7.5 and 10 mg of the salt per ml of water remained clear for 24 hours at room temperature. A 15 mg/ml solution remained clear for 6 hours at room temperature.

Example 7 Lyophilization f m-AMSA Mono ~L-Lactate Acetone Solvate m-AMSA DL-lactate acetone solvate ~180 mg; prepared in Example 6) was dissolved in 24 ml sterile water with stirriny.
The resulting clear (pH 4.2) solution was passed through a 1 inch 0.45 micron Millipore filter. Two ml of the filtrate was placed in an 8.2 cc flint vial and the solution was lyophilized for 24 hours.
Addition of 2 ml of sterile water to the lyophilized vial gave a 7.5 mg/ml clear solution. The solution remained clear for at least 6 hours at 17aC.
Shaking of the solution on a low speed horizontal shaker gave a clear solution for up to 5 hours.

Example 8 Sterile Crystallization of the DL-Lactate Acetone Solvat:e of ~-AMSA
1. Slurry 1.O yram of m AMSA base in 10~ ml of acetone at 22-28C. A solu-tion or near soLu-tion is obtained in 10 minutes.
2. U~ing aseptic technique, pass the acetone ~olution throuyh a sterile Millipore~luoropor~ or Mi-tex~
~ilter. Collectt the ~iltra-te in a sterile glass or ~tain-less steel container.

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Wash the filter with 10 ml of acetone and add the filtered acetone to the filtrate. This is Solutlon A. Use Solution A in step 5 within 5 hours.
3. Dissolve 1 gram of DL-lactic acid (1.18 ml of 85~ DL-lactic acid solution); q.s. to 10 ml in acetone (100 mg/ml of DL-lactic acid). Stir for 5 minutes.
4. Using aseptic technique, pass the acetone solution of DL-lactic acid throuyh a sterile Millipore Fluoropore~or Mitex~filter. Collect the filtrate in a sterile glass or stainless steel container. This is Solution B. Do not wash the filter.
5. With moderate stirring, add 5.8 ml of Solution B to all of Solution A over a 1-2 minute interval.
This represents 2.5 equivalen~s (0.58 g) of DL-lactic acid.
Crystals should form in 10 minutes of stirring. If crystals do not form, sterile m-~MSA DL-lactate acetone solvate seed crystals may be added or the sides of the container may be scratched with a sterile glass rod to induce crystallization.

6. Stir an additional 1 hour after onset of crystallization.

7. Remove the crystals by Lint-free sterile filtration technique. Wash the crystals with L0 ml of acetone previously filtered through a sterile Millipore~-Fluoropore~or Mitex~filter.

8. Vacuum-dry the crystals at 50C for 16-24 hours. Expected yield of aL-lactate acetone solvate is 1.1 grams.
: IR as in FIG. 3 NMR as in FIG. 4. Shows ~0.7 mole acetone solva-ked to salt and approximatel~ 0.1 moLe lactyl lacta-te as impurity.
m.p. = 159-L66C (decomp).
% m-AMSA in salt - 72~ (based on HPLC assay).
Solubility in water = 25 mg/~l at room ~emperature.

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Example 9 Dry-fill Parenteral Formula~ion of m-~MSA DL-Lactate Acetone ._ Solvate Formula In~redient Per Vlal Sterile m-AMSA DL-lactate **0.02 gram of m-AMSA
acetone solvate, 40-60 mesh activity 1. Using aseptic technique, place the required amount of sterile 40-60 mesh m AMSA DL-lactate salt into sterile vials. Cap with sterile rubber enclosures. Seal with aluminum seals. Vials are stored in the dark until ready to be reconstituted.
2. For reconstitution, add a sufficient amount of sterile water for injection to give a 5 mg/ml m-AMSA
activity solution. The reconstituted solutions may be stored at 20-25C for 16 hours. Caution: Solutions of m-AMSA are incompatible with chloride, sulfate and phosphate ions. Insoluble salts form.

*The additlon of 100 mg of mannitol is found to decrease reconstitution time with water.
**The amoun~ of m-~MSA DL-lactate acetone solvate required is a function of the potency of the salt, overfill required and needle-syringe-vial holdup. For example, assuminy a product having 0.7 moles acetone per mole of salt, the m-AMSA content of such product is 74.46~. Thus to provide O.2 grams m-AMSA activity, one would need 0.27 yrams of 100~ pure m~MSA DL-lactate acetone solvate. This amount is then adjusted ~or the actual po-tency of produc~, over~ill required, e-tc.

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Example 10 Preparation of Crystalline m-AMSA D(-)-Monolactate Hemiacetonate 1. Slurry 1.O gram of m-AMSA base in 100 ml of acetone at 22-28C. A solution or near-solutlon is obtained in 10 minutes.
2. Using aseptic technique t pass the acetone solution of m-AMSA through a sterile Millipore~Fluoropore~
or Mite ~filter. Collect the Eiltrate in a sterile glass or stainless steel container.
Wash the filter with 10 ml of acetone and add the Millipore-filtered acetone to the filtrate. This is solution A. Use solution A in step 5 within 5 hours.
3. Dissolve l gram of D(-)-lactic acid in sufficient acetone to provide 10 ml of acetone ~olution (100 mg/ml of D(-~-lactic acid). Stir for 5 minutes.
4. Using aseptic technique, pass the acetone solu-tion of D(-)-lactic acld through a Millipore~Fluoropore or Mite~ filter. Collect the filtrate in a sterile glass or stainless steel container. This is solution B. Do not wash the filter.
5. With moderate stirring add 5.8 ml of solution B to all of solution A over a 1-2 minute interval. This represents 2.5 equivalents (0.58 g) of D(-)-lactic acid, Crystals should form in 10 minutes of stirring. If crystals do not form~ sterile m-AMSA D(-)-lactate acetone solvate seed crystals may be added or the sides of the container may be scratched with a sterile glass rod to induce crystallization.
6. Stir an addi~ional l hour a~ter onset o~
cry~tallization.
7. Remove the crystals by suitable llnt~ree sterile ~iltration technique. Wash the crystals with lO ml o~ acetone previously filtered throuqh a steriLe Millipore-Fluoropore or Mitex ~ilter.

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8. High-vacuum dry the crystals at 50C. for 16-24 hours. Usual yield of m-AMSA D (-) -monolactate acetone solvate is 1.1 grams.
~roperties: IR as shown in FIG. 5 NMR as shown in FIG. 6. Shows ~0.4 mole acetone solvated to salt.
m.p. (capillary, uncorrected): 180-184C.
(decomposition).
% m-AMSA in salt: 78.4% (based on HPLC assay).
Elemental Analysis: C, 59.47; H, 5.20;
N, 8.41; S, 6.46.
%H2O (KF) = 0.39.

Example 11 Lyophilizatlon of D(-)-Monolactate Acetonate of m-AMSA
If the procedure of Example 7 is repeated with the m-AMSA DL-lactate acetone solvate replaced by an equimolar amount of the m-AMSA D(-)-monolactate acetone solva-te pre-pared in Example 10, there is produced a lyophilized solid which can be reconstituted with water to form at leas-t a 3-5 mg/ml m-AMSA activity solution. The solid analyzes for 1 mole of m-AMSA per mole of D(~)-lactic acid and contains no acetone.

Claims (6)

1. A process for producing a stable, solid, water-soluble composition for reconstitution with water or aqueous vehicle as a stable solution of 4'-(9-acridinyl-amino)methanesulfon-m-anisidide which comprises the steps of (1) forming an aqueous solution of crystalline L(+)-monolactate hemiacetonate of 4'-(9-acridinylamino)-methanesulfon-m-anisidide, crystalline DL-mono-lactate acetone solvate of 4'-(9-acridinylamino)-methanesulfon-m-anisidide, containing from about 0.6 to 0.7 moles of acetone per mole of lactate salt or crystalline D(-)- monolactate hemiacetonate of 4'-(9-acridinylamino)methanesulfon-m-anisidide;
and (2) lyophilizing the so-produced aqueous solution.

2. The process according to claim 1 wherein the aqueous solution of step (1) is filtered prior to lyophilization.

3. A stable, solid, water-soluble pharmaceutical dosage form for reconstitution with water or aqueous vehicle as a stable solution of 4'-(9-acridinylamino)-methanesulfon-m-anisidide, said dosage form being prepared by the steps of (1) forming an aqueous solution of crystalline L(+)-monolactate hemiacetonate of 4'-(9-acridinylamino)-methanesulfon m-anisidide, crystalline DL-mono-lactate acetone solvate of 4'-(9-acridinylamino)-methanesulfon-m-anisidide containing from about 0.6 to 0.7 moles of acetone per mole of lactate salt or crystalline D(-)-monolactate hemiacetonate of 4' (9-acridinylamino)methanesulfon-m-anisidide;
and (2) lyophilizing the so-produced aqueous solution.

4. The dosage form of Claim 3 prepared from crystalline L(+)-monolactate hemiacetonate of 4'-(9-acridinylamino)methanesulfon-m-anisidide.

5. The dosage form of Claim 3 prepared from crystalline DL-monolactate acetone solvate of 4'-(9-acridinylamino)methanesulfon-m-anisidide containing from about 0.6 to 0.7 moles of acetone per mole of lactate salt.

6. The dosage form of Claim 3 prepared from crystalline D(-)-monolactate hemiacetonate of 4'-(9-acridinylamino)methanesulfon-m-anisidide.