IE51468B1 - Microcrystalline cisplatin and formulations containing it - Google Patents

Description

This invention relates .to a stable, rapidly soluble, microcrystalline fora of cisplatin, and to dry-mix formulations thereof, which, after reconstitution with sterile water, are used fay injection in the chemotherapy of cancer.

The platinum compounds are a unique group of compounds in the antineoplastic group of agents. They were first noted to have an antibiotic effect by Rosenberg and his colleagues in 1965 [Rosenberg, B. et al., Nature (London), 10 205 , 698-699 (1965)] and subsequently found by Rosenberg and his colleagues to be potent antitumor agents in animals [Rosenberg, B. et al., Nature (London), 222, 385-386 (1969)1.

Structurally they represent a complex formed by a central atom of platinum and surrounded by various arrange15 merits of chlorine atoms or ammonia groups in either a eis or trans planar relationship. Two of the more commonly studied pla tiara compounds are diagrammed below: Cl Cl Cis-Platinua (II) Diamminedichlorid® Cis-Platinum (CV) Diamminetetrachlorids As can be seen, the compound cis-platinum (II) diamminecichlcride has all its chloro and amino groups in a single plane. This compound, now known by the United States Adopted Name (USAN) cisplatin, has been synthesized according to the following 5 reaction: nh4ci KglPtCl^] + 2NHg-> cis-[Pt(NH3)2Cl2] * 2KC1 (see Kauffman, G. B. et al., in Inorganic Synthesis, J. Xleinberg (Ed.), pages 235-245, McGraw-Hill Book Co., Inc., New York, 1963].

Breusova-Baidala, Y. G. et al., in Akademia Nauk SSSR, No. 6, pp. 1239-1242 (June 1974), discuss the slow isomerization Of cis-platinum (ZZ) diamminediehloride in aqueous solution to the trans form.

Reithus, J. W. and Martin, D. S., in Journal of The American Chemical Society, 83, 2457-2462 (1961), describe the acid hydrolysis of cisplatin at 25*C and 35*C. These studies were conducted in aqueous solutions at concentrations of 1.5 x 10-3 m, 2.5 x 1θ“3 M and 5.0 x 10~3 M, which correspond to 0.-45, 0.75 and 1.5 mg./ml., respectively. The authors state that there was some ambiguity in locating the origin (i.e. zero point) for the hydrolysis curves because the samples required from 10 to 30 minutes to dissolve completely even at these low concentrations.

Rczencweig, H. et al., in Annals' of Internal' Medicine. 86, 803-312 (1977), review the results of various preclimcal and clinical investigations of the use of cisplatin in experimental tumors in animals as well as various types 5 of human tumors. They point out that the investigational drug, available to qualified investigators through the investigational Drug Branch of the Cancer Therapy Evaluation Program of the National Cancer Institute, was supplied as a white lyophilized powder in vials containing 10 ng. of cisplatin, 90 mg. of sodium chloride, 100 mg. of mannitol (O.S.P.) and hydrochloric acid for pH adjustment. When reconstituted with 10 ml. of sterile water for injection (O.S.P.), each ml. of the resulting solution would contain 1 mg. of cisplatin, 10 mg. of mannitol and 9 mg. of NaCl.

Talley, R. W. et al., in Cancer Chemotherapy Reports, 57, 465-471 (1973), describe the results of their Phase I clinical study of the use of cisplatin in the treatment of 65 human patients with a wide variety of neoplasms. As in the preceding publication, the drug was supplied to them by the National Cancer Institute in vials containing 10 iag. of cisplatin, 90 mg.' sodium chloride and 100 mg. of mannitol, for reconstitution with 10 ml. of sterile water.

Rossof, A. H. et al., in Cancer, 30, 1451-1456 (1972), describe the results of their use of cisplatin in the treatment of 31 human patients with a variety of tumor types. They state that the drug supplied by the National Cancer Institute 514 68 was manufactured by Ben Venue Laboratories, Inc. and contained, per vial, 10 mg. of cisplatin, 10 mg. (sic) of mannitol and 9 mg. (sic) of NaCl, and that the yellowish-white powder dissolved readily in 8-10 ml. of sterile water.

Certain information concerning the chemistry ar.d pharmaceutical formulation of cisplatin are given on pages 1-5 and 31-32 of the publication entitled CLINICAL BROCHURE, CIS-PLATINUM (II) DIAMMINEDICHLORIDE (NSC-119875), H. Handelsman et al., Investigational Drug Branch, Cancer Chemotherapy Evaluation Program, Division of Cancer Treatment, National Cancer Institute (Revised August 1974). Pages 31 and 32 thereof concern the formulation of cisplatin supplied gratis by the N.C.I. to clinicians for their clinical evaluation in the chemotherapy of cancer and read as follows: PHARMACEUTICAL DATA SHEET NSC-119875 Cis-Diamminedichloroplatinum (II) Dosage Formulation mg./vial : The contents of each 20 ml. flint vial appears as an off-white lyophilized cake. Each vial contains 10 mg. of NSC-119875; 90 mg. of Sodium Chloride; 100 mg. of Mannitol and Hydrochloric acid for pH adjustment.

Solution Preparation mg./vial : when reconstituted with 10 ml. cf Sterile Water for Injection, ’JSP, each ml. cf the 31468 resulting solution.will contain 1 mg. of NSC-119875, 10 mg. of Mannitol, and 9 mg. of Sodium Chloride having a pH range of 3.5-4.5..

Storaoe Stability The dry, unopened vials should he stored at refrigeration temperatures (4-8* C.). Intact vials have a provisional stability of one year when stored at refrigeration temperature (4-8® C.). Stability recommendations may be adjusted pending completion of a two-year shelf-life study. Reconstitution as recommended results in a pale, yellow solution which is stable for not more than one hour at room temperature (22* C.) when exposed to normal room illumination and not more than eight hours at room temperature (22® C.) when protected from light. Reconstituted solutions may form a precipitate after one hour at refrigeration temperature (4-8® e.).

Caution : The lyophilized dosage formulations contain no preservatives and therefore it is advised to discard solutions eight hours after reconstitution.

August, 1974 Clinical Drug Distribution Section Drag Development Branch The present invention provides a stable, microcrystalline fora of cisplatin which is rapidly soluble in water, and a process for its preparation. The present invention also provides a sterile, stable, dry-mix of said microcrystalline fora of cisplatin suitable for rapid reconstitution with sterile water and intravenous administration to man; said dry-mix optionally containing a sterile, nontoxic, pharmaceutically acceptable, inorganic source of chloride ions in an «mount equivalent to that produced by the presence of sodium chloride in a concentration of from 1 to 20 mgs., and preferably about 9 mgs., per mg. of microcrystalline cisplatin; said dry-mix also optionally containing a customary, harmless, physiologically acceptable excipient, which is preferably mannitol, in a concentration of from 2 mgs. to 150 mgs., and preferably about 10 mgs., per mg. of microcrystalline cisplatin; said dry-mix being completely soluble in sterile water within three minutes (and usually-within two minutes), at a concentration of mg. of microcrystalline cisplatin per ml. of sterile water.

There is also provided by the present invention a sterile, stable, dry-mix of microcrystalline cisplatin in a sealed container such as an ampul or vial, in unit dosage form, suitable for rapid reconstitution with sterile water and intravenous administration to man: said dry-mix formulation comprising, per ml. of sterile water to be used for reconstitution, from 0.1 to . 1 me., and preferably about 1 mg., of sterile microcrystalline cisplatin; said dry-mix optionally containing, per ml. of sterile water to be used for reconstitution, a sterile, nontoxic, pharmaceutically acceptable, inorganic source of chloride leas in an amount equivalent ta that produced, by the presence of from 1 to 20 mgs., and preferably about 9 mgs., of sodium chloride; said dry-mix also optionally containing, per ml. of sterile water to be used for reconstitution, from 2 to ISO rags., and. preferably about 10 mg., of a customary, harmless, physiologically acceptable excipient, which is preferably mannitol; said dry-mix being completely soluble in sterile water within three minutes (and usually within i5 two minutes), at a concentration of 1 mg. of microcrystalline cisplatin per ml. of sterile water.

There is further provided by the present invention a process for the preparation of microcrystalline cisplatin which comprises the consecutive steps of a) a first solution camprisizu? a liquid organic amido, and preferably a tertiary amide, and most preferably dimethylformamide, containing, by volume, from about 1% to about 22%, and preferably about LOT, of aqueous hydrochloric acid having a concentration of about 6 N to about 12 N, and preferably about 12 N: bj dissolving cisplatin ia said first solution in an amount of from about 10 to about 60 grams, and preferably about 40 grams, per liter of said first solution, to provide a second solution; c) admixing said second solution, with agitation, with from about 0.5 to about 5 volumes, and preferably from about 0.75 to about 2.5 volumes, and most preferably about 2 volumes, of water or dilute aqueous hydrochloric acid having a concen5 tration up to about 0.2 N, and preferably about 0.1 N, at a temperature of from about 10*C to about 40*C, and preferably at about.room temperature, to form microcrystalline cisplatin; d) recovering the macrocrystalline cisplatin by filtration; e) washing the recovered microcrystalline cisplatin with water or aqueous hydrochloric acid having a concentration up to about 0.2 N, and preferably about 0.1 N; f) optionally further washing the microcrystalline cisplatin with a non-reactive, water-miscible, volatile, organic solvent, preferably selected from (lower)alkanols and di(lower)alkyl ketones; and g) optionally drying the washed microcrystalline cisplatin.

Practical considerations dictate that a medicament which requires reconstitution with water to fern a solution before administration by a physician be rapidly soluble in the appropriate amount of water, so as to avoid time-wasting and tiresome periods of shaking by the physician or hia assistant. Cisplatin, as prepared by the usual manufacturing procedures typically requires 10-25 minutes to dissolve in water at a concentration of 1 mg./ml., even if first screened to 200 mesh. The same period of time is required to dissolve cisplatin at the same concentration in an aqueous vehicle containing 9 mg./ml. of sodium chloride and 10 mg./ml. of mannitol, or to dissolve a mixture ci cisplatin, -sodium chloride and mannitol (in a weight ratio of 1:9:10) in water at a concentration of 1 mg. cisplatin per al.

Cisplatin is commercially available at the present time for cancer chemotherapy under the trademark PLATINOL.

Xt is supplied in unit dosage fora in a vial as a lyophilized powder containing 10 mg. of cisplatin, 90 mg. af sodium chloride and 100 mg. of mannitol, and is to be reconstituted with 10 ml. of sterile water. Reconstitution of this product may be accomplished within three minutes of shaking. However, the manufacturing process requires lyophilization of the individual vials of an aqueous solution of cisplatin, sodium chloride, mannitol and dilute HCl, whieh is an exoensive and time-consuming batch process.

Thus, a commercial-sized lyophilization operation of, for example, 40,000 vials would require about 4-5 days for completion. This procedure includes loading the vials on the shelves of the chamber, freezing the solutions, evacuating the ehamber until lyophilization is complete, adjusting the temperature of the chamber to above room temperature to complete the drying, admission of air into the chamber, sealing the vials and unloading the chamber.

A typical sterile dry filling operation, on the other hand, utilizing a single filling machine to fill 200 mg. of solids par vial, may be expected to produce about 40,000 filled and sealed vials per 8-hour shift. In addition, because the solubility of cisplatin is only about 1 mg./ml., the cost of preparing dosage forms containing more than about 25 mg.

S1468 cf cisplatin per vial by lyophilization becomes prohibitive because of the large volume of water to be removed. Such dosage forms may, however, readily be prepared by sterile dry-filling techniques, further disadvantages of lyophilise5 tion include the possibility of a power failure during the long cycle period, which would normally mean that the entire batch of cisplatin must be discarded. Also, Hd removed during lyophilisation may corrode the lyophilizer chamber end system.

Both the N.C.I. Pharmaceutical Data Sheet for cisplatin and the Official Package Circular for PLATINOL (cisplatin) discussed above state that the unopened vial of lyophilized product must be stored at refrigerator temperature. Stability tests on microcrystalline cisplatin and dry-mix formulations thereof indicate good stability at room temperature. Stability tests of 3 batches of microcrystalline cisplatin each showed less than a It loss after aging 3 months at 56*C and 45*C, months at 37 *C and 10 months at 25 *C when packed in amber colored glass vials sealed with teflon coated rubber stoppers »nd nested in cardboard cartons. Less than a 1.7» loss occurred with macrocrystalline cisplatin packaged in amber glass vials and teflon coated rubber steppers, when tested under accelerated light conditions at room temperature for one month without cartons. (The word Teflon is a registered Trade Mark), 25 Stability tests were also conducted on wicrccrystalline cisplatin dry-mix formulations containing 10 mg. of microcrystalline cisplatin, 90 mg. of sodium chloride and 100 mg. of mannitol packaged in amber colored glass vials Sealed with teflon coated rubber stoppers. Potency losses observed after 1468 aging 2 and 3 months at 56 °C and 45 °C were less than 74; losses after 4 and 6 months at 37*C were less than 5%; and losses after 10 and 11 months at 25°C were less than 6%.

Microcrystalline cisplatin provided hy the present invention has a particle size distribution of at least about 804 in the 0-5 micrometer range and less than about 20% in the 5-20 micrometer range, with essentially no particles greater than 20 micrometers. When prepared under preferred conditions the microcrystall in cisplatin typically contains no particles greater than 10 micrometers. This particle size distribution is of the same order as cisplatin which has been lyophilized from dilute hydrochloric acid and is significantly smaller than the typical particle size of machine micronized pharmaceuticals. Table 1, below, shows the microscopic partiele size evaluation of three batches of microcrystalline cisplatin,· one batch of lyophilized cisplatin (from 0.07 N HCl) and a typical batch of commercial machine micronized benzathine cephapirin.

Table 1 Particle Size Distribution (%) Material Micrometers 0-5 5-10 10-20 10-730 Macrocrystalline cisplatin (No. 759) 96 4 Λ — Microcrystalline cisplatin (No. 315) 32 14 4 — Macrocrystalline cisplatin (No. 277) 85 15 0 — Lyophilized cisplatin (No. 276) 97 0 — Machine micronized benzathine 1 | cephapirin (No. 158) 11.3 55.5 3.4 1 S1468 Although particle site distribution studies indicate that the particle size of macrocrystalline cisplatin is of the same order as that of lyophilized cisplatin, and simple microscopic examination shows that macrocrystalline cisplatin differs markedly in particle size from regular (bulk) cisplatin, the situation as reversed in terms of crystal structure. X-ray powder diffraction patterns show that macrocrystalline cisplatin and lyophilized cisplatin are clearly different crystalline forms, and that macrocrystalline cisplatin and regular cisplatin are of the same crystalline form (minor differences in the diffraction patterns being due to difference in particle size, packing in the capillary, etc.}. Table 2 gives the data obtained from X-ray powder diffraction studies (filtered Cu Ka radiation, 1.54051 angstroms) of regular cisplatin, macrocrystalline cisplatin and lyophilized cisplatin.

Table 2 X-rav Data For Different Forms Of Cisplatin Sample Two Theta (Degrees) Relative Intensity Interplanar Spacings (Angstroms) 13.89 100 6.370 15.00 49 5.901 Regular Cisplatin 18.30 28 5.433 (No. 389) 24.10 11 3.690 26.84 40 3.319 28.37 18 3.143 38.30 3 2.348 12.51 5 7.070 12.76 5 6.932 13.88 100 6.375 Lyophilized Cisplatin 14.13 100 6.263 (No. 359) 19.90 6 4.458 20.19 €3 4.394 28.11 8 3.172 28.71 9 3.107 31.90 4 2.803 13.81 100 6.407 14.93 84 5.929 16.26 71 5.447 Microcrystalline Cisplatin 24.05 27 3.S97 (No. 705) 26.57 22 3.352 28.37 IS 3.143 30.35 13 2.943 33.14 15 2.701 In preparing the microcrystalline’cisplatin of the present invention, regular (bulk) cisplatin is first dissolved in a solution of a liquid organic amide and hydrochloric acid.

Suitable amides will be apparent to those skilled in the art, the requirements being stability of the amide and sufficient solubility of cisplatin in the amide-HCl mixture. Amides suitable for use in this process include, for example, formamide, N-methylformamide, Ν,Ν-dimethylformamide, N-ethylforraamide, Ν,Ν-diethylformaaide, N,N-diroethylacetamide, Ν,Ν-diethylaeetamide, N-(2-hydroxyethyl)acetamide, N-methyl-2-pyrrolidinone, and the like. He prefer to utilize tertiary amides such as the Ν,Ν-dialkylforaamides and Ν,Ν-dialkylacetamides. The most preferred amide is Ν,Ν-dimethylformamide. It is preferred that high quality amide be utilized in this process. In parallel experiments utilizing (a) reagent quality DKF and (b) low quality technical grade DMF, we found that the lower quality DMT decreased the yield of product by about 4% and increased the solubility time of the product to about five minutes. a* composition of the amide-HCl solution may vary from about *1* (volume) to about 20% (volume) of hydrochloric acid, and the concentration of the hydrochloric acid may vary from about 6 N to about 12 N. The optimum composition of the amide-BCl solution for any given amide can be readily determined by those skilled in the art by routine testing. With the preferred amide, Ν,Ν-dimethylformamide, we prefer to utilize an amide-BCl solution comprising about 90% (volume) amide and about 10% (volume) of about 12 N HCl. It should be noted that too high a concentration of HCl may cause sone degradation of the cisplatin.

Depending on the particular amide utilized and the composition of the anide-HCl solution, from about 10 to about 60 grams of cisplatin may be dissolved per liter of amide-HCl solution. With many amide-HCl solutions sigr.i5 ficantly more than 60 grams of cisplatin may physically be dissolved per liter, but we have found that subsequent crystallization from too highly concentrated solutions gives a product which will not completely dissolve in 3 minutes.

At the lower end, we have found that less than about 10 grams of cisplatin per liter usually gives significantly decreased yields and, of course, requires inordinately high volumes of solution for a given amount of product.

Using the preferred DMF-concentrated HCl solution (about 9:1 by volume), we prefer to utilize about 40 grams of cisplatin per liter. the crystallization step may be conducted at a temperature of fro® about 10*C to about 35®C. At the higher temperatures the yield of product is lower due to increased solubility.

At temperatures below about 10®C we have found that the product 20 often has solubility times in excess of 3 minutes. It is believed that this is due to the product being too quickly ’shocked· out of solution rather than somewhat more slowly growing the proper microcrystalline cisplatin. But this is only a theoretical concept and does not form part cf the invention. It is, of course, most convenient to conduct the crystallisation step at room temperature and, since excellent yields of high quality microcrystallme cisplatin are obtained at rocm temperature,(e.g. 20-25* C.), this is our preferred crystallization temperature.

Crystallization is effected by admixing the amide-HCl solution of cisplatin with from about 0.5 to about 5 volumes of water or dilute HCl having a concentration up to about 0.2 N. The cisplatin solution may be added to the water (or dilute aqueous ECI), or the converse. Each procedure gives substantially the same yield and quality of microcrystalline cisplatin. The optimum volume of water (or dilute aqueous HCl) to be admixed with the cisplatin solution depends on the particular amide utilized as well as the composition of the amide-HCl-cisplatin solution. The optimum volume for any given cisplatin solution may be determined by routine testing. Generally, we prefer to utilize about 1.5 to about 2.5 volumes of water (or dilute aqueous HCl) per volume of amide-HCl-cisplatin solution. When using the preferred OMF-eoneentrated ECI (9:1 by volume) containing about 40 grams of cisplatin per liter, we prefer to use about 2 volumes of water (er dilute aqueous SCI) per volume of DMF-HCl-cisplatin solution. It should be noted that the use of too great a volume of water (or dilute aqueous HCl) tends to also crystallize out impurities which were in the starting cisplatin, e.g., trassplatinum.

As pointed out above, micrccrystalline cisplatin may be crystallized from its amide-HCl solution by the addition of water or dilute aqueous HCl. The choice between the two is not critical, and we prefer to be guided by tne amount and concentration of HCl present in the amide-HCl-cisplatin solution. 51468 18 Thus, if that solution contained a relatively low amount of HCl, near the lower limit of about 1% of 6 N HCl, we would prefer to use approximately 0.2 N HCl to effect the crystallization. Conversely if the amiee-HCi-cisplatin solution contained a large amount of HCl, near the upper limit of ¾ of 12 N HCl, we would prefer to utilize water to effect the crystallization. When using our preferred DMF-concentrated HCl (9:1) containing about 40 grams of cisplatin per liter, we prefer to utilize approximately 0.1 N HCl to effect the lo crystallization.

The microcrystalline cisplatin provided by the present invention (after sterilization) may be packaged alone in a sealed container such as an ampul or vial, preferably in t unit dosage fora, for reconstitution with sterile water 15 4at least 1 ml. per mg. of microcrystalline cisplatin) to produce a solution suitable for intravenous administration. Alternatively, the microcrystalline cisplatin may be admixed with a sterile, nontoxic, pharmaceutically acceptable, inorganic source of chloride ions in an amount equivalent to that produced 2o fey the presence of sodium chloride in a concentration of from about 1 to about 20 mgs. (and preferably about 9 mgs.) per mg. of microcrystalline cisplatin. Preferably, the source of chloride ions is sodium chloride. Xn another embodiment, the sterile microcrystalline cisplatin may be admixed with a sterile, customary, harmless, physiologically acceptable excipient, which is preferably mannitol, in an amount of from about 2 mg. to about 150 mg. (and preferably about 10 mg.) per mg. of sterile microcrystalline cisplatin. in still another embodiment, the sterile microcrystalline cisplatin may be admixed with both the aforementioned source of chloride ion and excipient in the amounts mentioned. Each of these dry-mixes is then packaged ia a sealed container such aa an ampul or vial, preferably in unit dosage form, for reconstitution with sterile water (at least 1 ml. per ag. of microcrystalline cisplatin) to produce a solution suitable for intravenous administration. The aforementioned dry-mixes may be prepared by simple dry blending of the desired ingredients or by wet granulation techniques, both of which ere well known in the art. with wet granulation procedures, it is preferred that a granulation be made of all ingredients except the cisplatin and that, after drying,the granulation be admixed with the desired amount of microcrystalline cisplatin.

The microcrystalline cisplatin of the present invention, and dry-mixes thereof, are readily soluble in sterile water (at least 1 al. per al. of microcrystalline cisplatin) within about three minutes. The reconstituted solution, if not used immediately, should be stored at about ream temperature.

Refrigeration at temperatures below about 10 *C results ia crystallization of cisplatin which is not ia the microcrystalline fora. This cisplatin is exceedingly difficult to redissclve at room temperature, but solution can be obtained by heating ts about 35-40*C.

Cisplatin is an inorganic compound first noted to prevent replication of E. coli and subsequently found to possess antitumor activity. Tha drug exerts its effect of interfering with DMA synthesis by causing cross-linking of complementary strands of ON A. It has activity in a variety of tumor systems including LI210, Sarcoma 180, Welker 256 carcinosarcoma, DMEA induced 5X468 mammary tumors and ascitic BI 6 melanosarcoma. The compound is especially interesting in that it exhibits synergism with a large number of currently-used chemotherapeutic agents.

Largs animal toxicology studies showed renal tubular necrosis, enterocolitis, hone marrow hypoplasia and lymphoid atrophy.

Phase X studies have demonstrated the following toxicities: syelosuppression, renal insufficiency, high frequency ototoxicity and Gt intolerance. Currently used dosages with mild to moderately acceptable toxicity are in the range of €0-100 mg./a3 IV as a single doss or divided over 3-5 days, to be repeated at four-week intervals. Early clinical trials show soma responses to the drug in germinal cell tumors, lymphomas, sarcomasr breast and head, and neck carcinomas.

A dosage of 60 mg./m is roughly equal to 1.5 mg./kg. which in turn is roughly equal to 105 mg. /patient weighing 70 kg.

The microerystalline cisplatin of the present invention, or dry-mixes thereof, after reconstitution, are used in the same manner and for the same purpose as stated above and in the other publications and ia the voluminous medical literature cn this subject. As stated therein, frequent us· is made of concurrent therapy with other chemotherapeutic egents for best results. When desired, the solutions of the present invention may be added immediately before use to e sterile» pharmaceutically acceptable aqueous diluent such as glucose or saline. Administration is either by direct intravenous injection or by intravenous infusion.

Platinol is a Company for cisplatin.

Dareo* is a Industries for activated Millipore is a Corporation for membrane trademark of Bristol-Myers trademark cf Atlas Chemical carbon. trademark of the Millipore filters.

Example 1 Preparation Of Microcrystallme Cisplatin To a solution of 0.7 ml. of 1 M HCl and 6.3 ml. of dimethylformamide (DMF) was added 280 mg. of cisplatin, and the mixture was stirred for 1 hour without obtaining a complete solution. An additional 2 ml. of DMF and 0.7 ml. of concentrated HCl were added, and the resulting solution was stirred for 1 hour and then divided into two parts. (a) To one part of the above solution (4.9 ml.) was added 20 ml. of 0.1 N HCl, and the resulting precipitate was slurried for 15 minutes. The solids were recovered by filtration, washed with 1.5 ml. of 0.1 N ECI and 3 ml. of acetone, and dried in vacuo at 20*C for 18 hours. The yield, of microcrystalline cisplatin was 93 mg. (668). Karl Fischer 15 analysis showed the product to be free of water and NMR analysis showed it to be free of DMF and acetone.

Anal. Calc'd for PtHg^Clj·. H, 2.02; N, 9.34; Cl, 23.63 Fouad; H, 1.89; N, 9.33; Cl, 22.59 Ten mg. of the above microcrystalline cisplatin was weighed into a 17 ml. vial along with 90 mg. of NaCl and 100 mg. of mannitol. To this mixture was added 9.9 ml. of sterile water, and complete solution was obtained within 1 minute cf shaking. Another 10 mg. portion cf the above microcrystalline cisplatin was shaken with 10 ml. of an aqueous solution of NaCl (30 mg./10 ml.) and manr.itcl (100 mg./10 ml.) and dissolved completely within 1 minute. (fa) The other part of the above solution (4.8 ml.) was added to 20 ml. of 0.1 N HCl and the resulting precipitate was slurried for IS minutes. The solids were recovered by filtration, washed with l.S ml. of 0.1 N HCl and 3 ml. of acetone, end dried in vacuo at 20*C for 18 hours. The yield of microcrystalline cisplatin was 98 mg. (70%). A 10 mg. portion of this product was shaken with 10 ml. of an aqueous solution of NaCl (90 mg./10 ml.) and mannitol (100 mg./10 ml.) and dissolved completely within 1 minute.

Example 2 Preparation Of Microcrystalline Cisplatin Cisplatin (280 ag.) was dissolved in 7.0 ml. of a DMF-HC1 solution prepared by mixing 0.7 ml. of concentrated HCl and €.3 ml. of DMF. The solution was stirred for 1 hour and then 15 14 ml. of 0.1 N HCl was added. The resulting precipitate was slurried for 15 minutes and the solids were then recovered b.y filtration, washed with 2 ml. of O’C 0.1 N HCl and 4 ml. of acetone, and dried in vacuo at 20*C for 20 hours. The yield of aicroezystalline cisplatin was 225 mg. (801). A 19 mg. sample, of this product was shaken with 10 ml. of an aqueous solution of NaCl (90 mg./10 ml.) and mannitol (100 mg./10 ml.) and dissolved completely within 3 minutes. Another 10 mg. sample of the product was mixed with 90 mg. of NaCl and 100 mg. of mannitol, and this dry-mix formulation was completely soluble in 9.9 ml. of water within 3 minutes.

Example 3 Preparation Of Microcrystalline Cisplatin Cisplatin (210 mg.) was added to 3 al. of a DMF-HC1 solution prepared by mixing 0.3 ml. of concentrated HCl and 2.7 ml. of DM?. Complete solution was not obtained after hour of stirring so an additional 0.1 ml. of concentrated HCl and 0.9 ml. of DMF was added. The resulting solution was stirred for 1 hour and 8 ml. of 0.1 N HCl was then added. The resulting precipitate was slurried for 15 minutes and the solids were then recovered by filtration, washed with 1.5 ml. of 0.1 N HCl and 2 ml. of acetone, and dried in vacuo at 20®C for 20 hours. The yield of microcrystalline cisplatin was 162 mg. (77¾).

Example 4 Preparation Of Microcrystalline Cisplatin Cisplatin (210 mg.) was dissolved in 5.25 ml. of a solution of DMF-HC1 (9:1). The solution was stirred for 1 hour and .5 ml. of 0.1 N HCl was then added. The resulting precipitate was slurried for 15 minutes and the solids were then recovered by filtration, washed with 1 ml. of 0.1 N HCl and 2 ml. of acetone, and dried in vacuo at 20*C for 18 hours. The yield of microcrystalline cisplatin was 168 mg. (80¾). Ten mg. cf this product was shaken with 10 ml. of an aqueous solution of NaCl (90 ag./ΙΟ ml.) and mannitol (100 mg./10 ml.) and dissolved completely within 2 minutes. An additional 10 mg. of this product was mixed with 90 mg. of NaCl and 100 mg, of mannitol and the dry-mix was completely soluble in 9.9 ml. of sterile water within 2 minutes of shaking.

Example 5 Preparation Of Microcrystalline Cisplatin Cisplatin (1.0 g) was dissolved in 25 ml. of DMF-HC1 (9:1) solution. The clear solution was stirred for 1 hour under a nitrogen atmosphere and 50 ml. of 0.1 N HCl was then added. The resulting precipitate was slurried for 15 minutes and the solids were then recovered by filtration and washed with 5 ml. of 4*C 0.1 N HCl and 10 ml. of acetone. About one-fourth of the solids were dried in vacuo at 40*C for IS hours to give 0.120 g of product. The remainder of the solids were dried in vacuo at 20*C for 18 hours to give 0.682 g of product. Total yield of microcrystalline cisplatin was 0.802 g (808).

A ten mg. sample of each of the dried products was shaken with 10 nl. of an aqueous solution containing NaCl (90 ag./ΙΟ al.) and mannitol (100 mg./10 ml.), and each 20 was found to be completely soluble within 3 minutes.

Thin layer chromatography (TLC) of the two products did not detect any impurities in either. High performance liquid chromatography (HPLC) of the two products indicated a potency of 984 mcg./mg. for the material dried at 40*C and a potency of 1027 mcg./mg. for the material dried at 20*C.

Anal. Calc’d for PtH.N.Cl,': tf ·· f 2.02; N, 9.34; Cl, 23.63 (Dried at 40C) Found: H, 1.77; N, 9.31; Cl, 23.29 (Dried at 20“C) Found: H, 1.79; M, 9.21; Cl, 23.13 Example 6 Preparation Of Microcrystalline Cisplatin Cisplatin (2.5 g) was dissolved in 62.5 ml. of DMF-HC1 solution (prepared by dissolving 15 ml. concentrated HCl in 135 al. cf DMF). The solution was stirred fcr 1 hour under nitrogen ano 125 ml. of 0.1 N HCl was then added. The 1° resulting precipitate was slurried for 15 minutes and the solids were then recovered by filtration, washed with 12 ml. of 0.1 N HCl and 25 ml. of acetone, and dried in vacuo at 20*C for 18 hours. The yield of microcrystalline cisplatin was 2.0 g (80$). A 10 mg. sample cf the product was shaken with 10 ml. of an aqueous solution containing NaCl (90 mg./10 ml.) and mannitol (100 mg./10 ml,), and was completely soluble within 2 minutes.

A dry-mix formulation was prepared by thoroughly mixing 750 mg. of the above product (290 mesh), 5.75 g cf NaCl' (200 mesh) and 7.5 a of mannitol (200 mesh).

Example 7 Preparation of Sterile, Pyrogen Free Sodium Chloride NaCl (18.5 g) was dissolved in 62 ml. of distilled water.

To this solution was added 1.85 g of activated carbon (Darco K3), and the mixture was starred fcr 0.5 heur. The carbon was removed by filtration through hard filter paper and the filtrate was slowly added to 62 ml. of rapidly stirred concentrated HCl. The resulting precipitate was slurried for 0.5 hour, recovered by filtration through hard filter paper and dried at 100*C for 18 hours. The yield of product was 13.8 g (75%).

Example 8 Preparation Of Sterile, Pyrogen-Free Mannitol Mannitol (10 g) was dissolved in 67 ml. of distilled lo water. Activated carbon (1.0 g, Darco KB) was added and the mixture was stirred for 0.5 hour. The mixture was then filtered through hard filter paper and the filtrate was slowly added to 335 ml. of rapidly stirred acetone. The resulting precipitate was slurried for 0.5 hour, recovered by filtration through hard filter paper and dried at 100*C for 18 hours. The yield of product was 8.0 g (80*).

Example 9 Preparation Of Sterile Dry-Fill Cisplatin Fog Injection (10 Hq. Cisplatin Per Vial) A. Preparation Of Sterile Microcrystalline Cisplatin Precautions All personnel involved with handling of this product should protect themselves as follows: (a) Wear face mask, eye protection, gloves and protective clothing during manufacturing, processing 10 and packaging. (b) Avoid any and all contact with the drug by inhalation os dermal contact. (c) Clean all equipment and the manufacturing area thoroughly to rsaove a possible drug contamination.

Procedure 1. Place 90 ml. of dimethylformamide * into a suitable glass container and maintain an overlay of nitrogen. Start' and maintain rapid stirring. Slowly add 10 ml. of concentrated hydrochloric acid, U.S.P.*’ Maintain the temperature in the range of 20 to 27°C.

*Tha dimethylformamide should be free of dimethylamine and approximately equivalent in purity to Burdick and Jackson Laboratories, Bimethylformamide, Distilled la Glass or Fishes Certified (ACS) Dimethylformamide, cist D-113. 00 U.S.?. herein stands for United States Pharmacopeia 2. Continue to rapidly stir the 100 roi. of freshly prepared solution under a blanket of nitrogen maintaining the temperature in the range of 20-27*c. 3. Slowly add 4 grams of cisplatin over a 5-minute interval. Continue rapid stirring under a blanket of nitrogen for 1 hour. A solution or near solution is obtained. 4. Using nitrogen pressure pass the solution through a sterile 0.22 micrometer Millipore filter into a suitable sterile, pyrogen-free glass container using aseptic technique in a sterile area.

. To the filtrate maintained under rapid stirring, adc, over a 5-minute interval, 200 ml. of 20-27*C sterile, pyrogenfree O.llJ hydrochloric acid. Sense, yellow microcrystals fora. Stir for 15 minutes. 6. Using aseptic technique, isolate the crystals by suitable filtration. Suck the filter cake to an apparent dryness. Do not pass excess air through the filter cake.

Retain the filtrate. 7. Mash the filteT cake with 10 ml. of 20-27*C, sterile, pyrogen-free 0.1N hydrochloric acid. Add the wash to the Step ( filtrate. Suck the filter cake to an apparent dryness. Do net pass excess air through the filter cake.

Wash the filter cake with 20 ml. of sterile, pyrogen-free scetcne. Add the wash to the filtrate. Suck the filter cake to an apparent dryness. Do nee pass excess air through the filter cake. (Save the combined filtrates. Recovery of cisplatin from the filtrate is described in Step 9 which follows.) 8. Using aseptic technique, remove and high-vacuum dry the aicrocrystalline cisplatin (in the absence of light) for 24 hours at 37-42'C. yield: Approximately 3.3-3.5 grams (80-864 yield). Store the yellow microcrystals in a suitable, sterile, pyrogen-free amber glass container capped with a metal screw csd containing a teflon or polyethylene liner at controlled i0 Room Temperature in the absence of light. 9. (a) Cool the filtrate of Step 7 above with stirring to 0-4*C. Aseptic conditions are not required. Hold the mixture without stirring for 48 hours at 0-4*C.

Golden crystals are deposited. Remove the crystals 15 by filtration. Wash with 20 ml. of acetone and highvacuum dry the crystals (in the absence of light) at 37-42*C for 24 hours, yield: Approximately 0.2 g. (5% yield). These crystals do not have the solution properties of the microcrystalline form and should be 2Q reworked via the above procedure to yield microcrystalline cisplatin. (b, The platinum compounds remaining in the filtrate may ba recovered by distillation of the water and dimethylformamide.

Properties Cf Sterile Microcrystallir.e Cisplatin As Prepared 5v Above Procedure 1. H.P.L.C. Assay; Single peak of 2.3 minutes retention time (102S meg./mg.). 2. IR: Consistent for structure. 3. NMR: In T.P.A.; no evidence of acetone or dimethylformamide. 4. Elemental Analysis: Consistent for formula; product appears anhydrous.

. Crystal Morphology: At 250X in mineral oil using the polarizing microscope, the microcrystals appear as very small rods showing specific extinction. The parent cisplatin appears as very large irregular plates (possibly hundreds of times the size of the microcrystals) showing a birefringence of the eolor spectrum.

B. Preparation Of Sterile Sodium Chloride 1. Place 90 ml. of Sterile· Hater for Injection, U.S.P. Into a suitable glass container. Start stirring and maintain the temperature in the range of 20-26*C. Add and dissolve 27 grams of sodium chloride. Maintain stirring until solution is obtained. 2. Continue stirring and add 2.7 grams of Sareo XB activated carben. Maintain stirring for 1.0 hour. 1468 3. Remove the carbon by filtration. Wash the carbon cake with 5 ml. of Sterile Mater for 'Injection. Add the wash to the filtrate. 4. Using nitrogen pressure and aseptic technique, pass the filtrate through a suitable, sterile, pyrogen-free 0.22 micrometer Millipore filter into a suitable, sterile, pyrogenfree glass container. This is Solution A.

. Using aseptic technique, add 5 volumes (approximately 550 ml.) of acetone which has been filtered through a sterile 0.22 micrometer Millipore filter to the rapidly stirring Millipore filtered Solution A over a 10 minute interval. (Alternatively, Solution A say be added to 550 ml. of rapidly stirring acetone which has been filtered through a sterile 0.22 micrometer Millipore filter.) Crystals form. 6. Maintain stirring at room temperature for 0.5 hour. 7. Remove the crystals by suitable filtration using aseptic technique. 0. Hash the crystals on the filter with two 40 ml. portions of acetone Which has been filtered through a sterile 0.22 micron Millipore filter.

, Using aseptie technique, remove the crystals from the filter and air-dry at 115-12S*C for 24 hours. Yield: Approximately 21.5 grams (SO* yield).

. Store the crystals in a suitable, sterile, pyrogenfree amber glass container capped with a metal screw cap containing a teflon or polyethylene liner.

Properties Of Sterile Sodium Chloride Prepared By 5 Above Procedure 1. Acetone not detectable by NMR. 2. Water (Karl Fisher) « Typically about 1» C. Preparation Of Sterile Mannitol 1. Place 90 ml. of Sterile Water for Injection, U.S.P. 10 into a suitable glass container. Start stirring and maintain the temperature in the range of 20-26*C. Add and dissolve 13.6 grass of mannitol. Maintain stirring until solution is obtained. 2. Continue stirring and add 1.4 grams of Dareo KB 15 activated carbon. Maintain stirring for 1 hour. 3. Renove the carbon by filtration. Wash the carbon cake with 5 ml. of Sterile Hater for Injection, U.S.P. Add the wash to the filtrate. 4. Using nitrogen pressure and aseptic technique, pass 20 the filtrate through a suitable, sterile, pyrogen-free 0.22 micrometer Millipore filter into a suitable sterile, pyrogenfree glass container. 5146b . Using aseptic technique, acd to the filtrate, with rapid stirring and over a 10 minute interval, 300 ml. of acetone which has been filtered through a sterile 0.22 micrometer Millipore filter. Crystals form. (Alternatively, the filtrate may be added over a 10 minute interval to 500 ml. of rapidly stirring acetone which has been filtered through a sterile 0.22 micrometer Millipore filter.) Maintain stirring for 0.5 hour at room temperature. 6. Remove the crystals by suitable filtration using aseptic technique. 7. Hash the crystals on the filter with two 20 ml. portions of acetone which has been filtered through a sterile 0.22 micrometer Millipore filter.

S. Using aseptic technique remove the crystals from 15 the filter and air~dry at 100-115*C for 24 hours. Yield: Approximately 11.4 grams (84% yield). 9. Store the crystals in a suitable, sterile, pyrogenfree amber glass container capped with a metal screw cap containing a teflon liner.

Properties Of Sterile Mannitol Prepared By Above Procedure 1. No acetone detected by NMR. 2. Hater (Karl Fisher) » Typically about 0.4 - 1% 0. Preparation Of A Sterile Granulation Of Mannitol Ann Sodium Chloride For Use In sterile Dry-Fill Macrocrystalline Cisplatin For Injection Formula Per 10 mg. Cisplatin vial Per Ten Thousand 10 mg. Cisplatin Vial Sterile Mannitol 0.1000 Gram 1000.00 Grams Sterile Sodium Chloride 0.0900 Gram 900.00 Grams Sterile Water For Injection, 0.025· ml 250.00 ml U.S.P *The amount o' water used may vary as a function of obtaining a wet granulation having suitable consistency. The water is removed during processing.

Manufacturing Instructions (Observe Safety Precautions Listed Below) 1. Using aseptic technique and appropriate sterile pyrogen-free equipment, separately mill the sterile, pyrogenfree mannitol and the sterile, pyrogen-free sodium chloride through a 40 mesh screen. 2. Using aseptic technique, place the requires amounts of milled sterile, pyrogen-free mannitol and sodium chloride into an appropriate sterile, pyrcgen-free blender. A jacketed vacuum V-Blender or Cone Blender equipped with an agitator bar is desirable. Blend for one hcur. 3. In small increments add a sufficient amqunt of sterile, pyrogen-free Water for Injection, U.S.P.· through the agitator bar with the blender rotating until a granulation of suitable consistency is formed. After each addition of water for injection, run the agitator bar for two 5-minut periods during a ene-'nalf hour blendinc period.

•NOTE: The amount of water shown in the formula was determined in a small scale laboratory run. Depending on the equipment used for producing larger batches, the amount of water required to prepare a granulation with suitable consistency may vary from the indicated amount. 4. When a suitable granulation is obtained continue the blender rotation with agitator bar turned off and vacuum· dry in the blender with the heating water in the jacket set at 50-70“C for 24 hours or until the water content is belew 0.3%.

Alternatively, the blend may be removed from the blender and dried at 50*C-60*C in a sterile 0®vine vacuumeven for 48 hours.

. Using aseptic technique pass the dried blend through a suitable sterile, pyrogen-free mill equipped with a sterile pyrogen-free 60 mesh or equivalent screen. ¢. place the milled, sterile granulation into a suitable sterile, pyrogen-free blender and blend for a half hour or until content uniformity is obtained. The powder may be assayed for chloride content over time as a check for content uniformity. 7. Store the powder in suitable sterile, pyrogenfree amber glass containers capped with a metal screw cap containing a teflon or polyethylene liner. Alternately, the required amount of sterile blend may be left in the blender and the required amount of microcrystalline cisplatin added to produce Cisplatin for Injection.

Safety Precautions All personnel involved with handling of this product should observe the precautions set forth above, in Example 9.

E. Sterile Dry-Fill Cisplatin for Injection (10 Hg.

Clsolatln Per Vial IXabel Claim is 10 Mg. of Cis-Diamminedlchloro Platinum II (Cisplatin) Per Vial] Precautions All personnel involved with batching of this product should observe the precautions set forth above, in Example 9.

Formula Ingredient Sterile, Pyrogen-Free Microcrystalline Cisplatin Sterile, Pyrogen-FSree Sodium Chloride (40 mesh) Sterile, Pyrogen-Free Mannitol (40 mesh) Per Vial Per 100 Vials *0.0100 g. 0.0900 g. 0.1000 g. 1.00 g. 9.00 g. .00 g. 0.2000 g. 20.00 g. •This weight of cisplatin assumes a potency of 1000 meg./mg. To calculate the amount of cisplatin to use, apply the following formula: 1000 x 0.0100 g.

Potency of cisplatin in meg./mg.

Grams of cisplatin per vial Manufacturing Instructions, 1. Using aseptic technique and appropriate sterile pyrogen-free equipment, separately mill the sterile, pyrogen· free mannitol and the sterile, pyrogen-free sodium chloride through a 40 mesh screen. 2. Mix the required amounts of screened, sterile, pyrogen-free sodium chloride and mannitol in appropriate sterile, pyrogen-free mixing or blending equipment for 1 hour. A V-Blender or Cone Blender equipped with an agitator bar is desirable. 3. Pass the microcrystalline cisplatin through a sterile 40 mesh screen to eliminate any lumps. To the blender containing the mixture from the preceding step (or the granulation from Step D, above) add the required amount of sterile, pyrogen-free microcrystalline cisplatin in three, separate and about equal increments. Blend for 30 minutes after each addition. Pass the mixture through a sterile 40 mesh screen and return to the blender. Mix for 30 minutes or longer until a uniform mixture is realized. 4. Drop the blend into suitable, sterile, pyrogenfree amber glass containers capped with a metal screw cap containing a teflon liner. Store the bulk in the dark.

. Fill the required .amount of mixture into suitable, sterile, pyrogen-free amber glass vials. Cap and seal with suitable, sterile, pyrogen-free teflon coated rubber stopper and seal with aluminum caps. Store the vials in the dark. 6. The 10 mg, cisplatin vial must be reconstituted with not less than 10 ml. of Sterile Water for Injection, U.S.P. at 22-30*C. A clear solution should be obtained within 3 minutes of shaking. A pH of 4.0 to S.S is noted. Cisplatin solutions at a concentration greater than 0.5 me./ml. should not be refrigerated since the cisplatin will cryst&lize out of solution.

Sieve Mesh Sizes - The mesh numbers herein relate to the United States Standard Sieve Series.

Claims (19)

Claims

1. Stable, microcrystalline cisplatin having a particle size distribution of at least SO* nailer than 5 micrometers, less than 20% in the range 5 of 5 to 20 micrometers and essentially no particles larger than 20 micrometers; the crystalline fora of said microcrystalline cisplatin being readily differentiated from that of lyophilized cisplatin by its x-ray powder diffraction pattern; and said microcrystalline cisplatin being 10 completely soluble in water within three minutes et a concentration of 1 ag. per ml.

2. The microcrystalline cisplatin of Claim 1 having an x-ray powder diffraction pattern substantially as follows: Two Theta Relative {Degrees) Intensity Zntsrplanar Spacings (Angstroms) 13.81 100 6.407 14.93 84 5.929 16.26 71 5.447 24.05 27 3.697 26.57 22 3.352 28.37 16 3.143 30.35 13 2.943 33.14 15 2.701

3. The microcrystalline cisplatin of Claim 1 or 2 wherein said microcrystalline cisplatin is sterile.

4. Sterile, stable, microcrystalline cisplatin in a sealed container in unit dosage form, reconstitutable with

5. Sterile water within three minutes at a concentration of 1 mg. of microcrystalline cisplatin per ml. of sterile water, and suitable for intravenous administration to man; said microcrystalline cisplatin having a particle size distribution of at least 80% smaller than 5 10 micrometers, less than 20% in the range of 5 to 20 micrometers and essentially no particles larger than 20 micrometers; the crystalline fora of said microcrystalline cisplatin being readily differentiated from that of lyophilized cisplatin by its x-ray powder diffraction pattern 15 5. The sterile unit dosage form of microcrystalline cisplatin of Claim 4 wherein said microcrystalline cisplatin has an x-ray powder diffraction pattern substantially as specified in claim 2.

6. A sterile, stable, dry-mix of microcrystalline cisplatin in a sealed container in unit dosage fora, reconstitutable with sterile water within three minutes at a concentration of 1 mg. of microcrystalline cisplatin per ml. 5 of sterile water, and suitable for intravenous administration to man; said dry-mix also containing a sterile, non-toxic, pharmaceutically acceptable, inorganic source of chloride ions in an amount equivalent to that produced by the presence of sodium chloride in a concentration of from 1 to 10 20 mgs. per mg. of microcrystalline cisplatin; said microcrystalline cisplatin being as specified in claim 1.

7. The dry-mix of Claim 6 wherein the inorganic source of chloride ions is sodium chloride. ·. The dry-mix of Claim 7 wherein the sodium chloride is 15 present at a concentration of about 9 mg. per mg. of microczysta.lline cisplatin..

8. 9. A sterile, stable, dry-mix of aicrocrystalline ciaplatin in a sealed container in unit dosage form, reconstitutable with sterile water within three minutes at a concentration of 1 mg·, of microcrystalline cisplatin per ml. of sterile water, and suitable for intravenous administration to man; said dry-mix also containing a customary, harmless, physiologically acceptable excipient in a concentration of 5 from 2 mgs. to 150 mgs. per mg. of microcrystalline cisplatin; said miereorystalline cisplatin being as specified in claim 1.

9. 10. The dry-mix of Claim 9 wherein the excipient is mannitol. 10

10. 11. The dry-mix of Claim 10 wherein the mannitol is present at a concentration of about 10 mg. per mg. of microcrystalline cisplatin.

11. 12. A sterile, stable dry-mix of aicrocrystalline cisplatin in a sealed container in unit dosage form, recon15 atitutable with sterile water within three minutes at a concentration of 1 mg. of microcrystalline cisplatin per m?, of sterile water, and suitable for intravenous administration to man; said dry-mix also containing both a sterile, nontoxic, pharmaceutically acceptable, inorganic source cf chloride ions is an amount equivalent to that produced by the presence of sodium chloride in a concentration of from 1 to 20 mgs. per ag. of microcrystalline cisplatin and a customary, harmless, physiologically acceptable excipient in a concentration of from 2 mgs. to 5 150 mgs. per mg. of microcrystalline cisplatin; said microcrystalline cisplatin being as specified in claim 1.

12. 13. The dry-mix of Claim 12 wherein the inorganic source of chloride ions is sodium chloride and the excipient is mannitol. 10 14· The dry-mix of Claim 13 wherein the sodium chloride is present at a concentration of about 9 mgs. per mg. of microcrystalline cisplatin and the mannitol is present et a concentration of about 10 mgs. per mg. of microcrystalline cisplatin. 15 15. The dry-mix of claim 6, 7, 8, 9, 10, 11, 12, 13 or

13. 14 wherein the microcrystalline cisplatin has an x-ray powder diffraction pattern substantially as specified in claim 2. 16. A process for preparing the microcrystalline cisplatin of claim l, comprising the consecutive steps of a) providing a first solution comprising a liquid organic amide containing, by volume, From IS to 5 20^ of aqueous hydrochloric acid having a concentration of from 6 N to 12 N; b) dissolving cisplatin in said first solution in an amount of from 10 to 60 grams per liter of said first solution, to provide a second solution; 10 c) admixing said second solution, with agitation, with from 0.5 to 5 volumes of water or dilute aqueous hydrochloric acid having a concentration up to 0.2 N at a temperature of from 10°C to 40°C to form microcrystalline cisplatin;

14. 15 d) recovering the microcrystalline cisplatin by filtration; e) washing the recovered microcrystalline cisplatin with water or aqueous hydrochloric acid having a concentration up to 0.2 N; 2o f) optionally further washing the microcrystalline cisplatin with a non-reactive, water-miscible, volatile organic solvent; and g) optionally drying the washed microcrystalline cisplatin. 25 17. The process of Claim 16 wherein the liquid organic amide is a tertiary amide.

15. 18. A process for preparing the microcrystalline cisplatin of claim 1, comprising the consecutive steps of a) providing a first solution comprising a liquid 30 organic tertiary amide containing, by volume, from 5% to 15% of aqueous hydrochloric acid having a concentration of about 12 N; b) dissolving cisplatin in said first'solution in an amount of about 40 grams per liter of said first solution, 35 to provide a second solution; c) admixing said second solution, -with agitation, with 0.75 to 2.5 volumes of water or dilute aqueous hydrochloric acid having a concentration up to 0.2 N at about room temperature, to form micro51468 crystalline cisplatin; d) recovering the microcrystalline cisplatin by filtration; a) washing the recovered microcrystalline cisplatin with aqueous hydrochloric acid having a concentration up to 0.2 N; f) optionally Further washing the microcrystalline cisplatin with a non-reactive, water-miscible, volatile organic solvent; and g) optionally drying the washed microcrystalline cisplatin.

16. 19. The process of Claim 18 wherein the liquid tertiary organic amide is Ν,Ν-dialkylformamide, an N,N-dialkylacetamide or N-methyl-2-pyrrolidinone.

17. 20. A process for preparing the microcrystalline cisplatin of claim 1, comprising the consecutive steps of a) providing a first solution comprising dimethylformamide containing, by volume, about 10% of aqueous hydrochloric acid having a concentration of about 12 N; b) dissolving cisplatin in said first solution in an amount of about 40 grams per liter of said first solution, to provide a second solution; c) admixing said second solution, with agitation, with about 2 volumes of dilute aqueous hydrochloric acid having a concentration'of about 0.1 N at about room temperature, to form microcrystalline cisplatin; d) recovering the microcrystalline cisplatin by filtration; a) washing the recovered microcrystalline cisplatin with aqueous hydrochloric acid having a concentration of about 0.1 N; f) optionally further washing the microcrystalline cisplatin with a non-reactive, water-miscible, volatile, organic solvent selected from (lower)alkanols and di(lower) alkyl ketones; and g) optionally drying the washed microcrystalline cisplatin.

18. 21. Microcrystalline cisplatin substantially as hereinbefore described in any one of Examples 1 to 6 or 9.

19. 22. A process for the preparation of microcrystalline cisplatin substantially as hereinbefore described in any one of Examples 1 to 6 or 9.