SA93140248B1 - crystalline amifostine - Google Patents

Abstract

Abstract: The present invention relates to a sterile, stable, vacuum-dried, crystalline amifostine formulation and optionally, pharmaceutically acceptable excipient(s) formulation(s) typically. The formulations of the present invention exhibit enhanced stability at temperatures ranging from about 4 °C to about ambient temperature for a period of at least two years for amifostine formulations. Solid and dried in vacuum. Reconstituted compositions of the present invention are suitable for administration to humans as a radiological or chemical shielding agent.

Description

SY - Crystalline amifostine formulations, methods of preparation and use (aa gl) Complete

BACKGROUND OF THE INVENTION The present invention relates to compositions of 5-? - SY (aminopropylamino) ethyl SLB hydrogen phosphorothioate S-2-(3-aminopropylamino) ethyl dihydrogen phosphorothioate (amifostine) Sterile, crystalline, particle-free Allg provides improved stability.

© compound 8- 7-(-aminopropylamino)ethyl dihydrogen phosphorothioate (which is identified by Lad as amifostine, ethiofos, Ethyol®, NSC 1, 28-2721 77) is disclosed. which will be referred to hereinafter as “amifostine”) and other aminoalkyl dihydrogen phosphorothioates in US No. 7847476 Piper Aul et al. This patent reveals Lad

0 The known process for making a crystalline form of the drug amifostine and is incorporated herein by reference. This crystalline form of amifostine has been shown to be relatively stable at room temperature for several years and also at 0°C for several months. These compounds were initially developed as anti-radiation agents (radiation shielding materials) to be used specifically against X-rays or atomic radiation that might be encountered during military conflicts.

0 In addition to its usefulness as a military antiradiation agent; Amifostine has shown excellent utility as a radioprotective and non-drug chemical shielding agent; Any protective material for the undesirable adverse effects that appear during the use of radiation therapy in treatment

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cancer and the use of chemotherapeutic agents; For example . Alkylating agents: 15 such as cyclophosphamide, cisplatin, carboplatin, doxorubicin and its derivatives, mitomycin and its derivatives. Similarly, amifostine has been reported to have been used experimentally to protect HIV-infected patients from adverse side effects of 3'-azido-3'-deoxythymidine (AZT) treatment. . Amifostine and its derivatives exert their protective effects without significantly affecting the beneficial properties of the given therapeutic agents. This is in part due to selective uptake of the protective thiol in normal tissues. The expression “amifostine substance” as used herein refers to its pre-vacuum-dried 0 or previously vacuum-dried state which is present on an “as is” basis in the form of trihydrate. References shall be made to sterile vacuum-dried compositions Cua (amorphous) that the form covered by the present invention will be referred to as "crystalline amifostine" in order to distinguish between the two forms. If not specified otherwise ell) said quantities will be calculated In this patent on the German smoothest M1.Although amifostine has many beneficial properties, many difficulties were encountered in attempting to obtain a suitable, stable and sterile dosage formulation.1 The present method for manufacturing and packaging of amifostine includes water filling steps1 Sterile in pre-sterilized vials comprising amifostine to a predetermined volume; cooling of the vials and their contents; and removal of 0 solvent by lyophilization to produce dry amifostine in a predetermined amount in each vial.

Pa. M. Lashman et al. the Theory and Practice of Industrial Pharmacy 962-63, 1986 Ref. 2Z This avoids substantial practical problems associated with filling excess and solid amifostine by using what is called a "dry fill" or "powder filling" method. Such problems include the difficulty in manual handling of powders; the need to grind powders to an acceptable particle size and flowability; the difficulty in maintaining sterile, particle-free conditions; Difficulty in supplying the dose. 0 min of solid amifostine in each vial. of amifostine; This amorphous form is Ulla on the other hand. For the available formulation, the oll produced by lyophilization must be kept thermally unstable. As a result, transport at about -0°C to Yeo on this lyophilized formulation at about -70°C to avoid decomposition of the formulated product. The need for low temperature at00 transport and storage is a drawback to the dried forms of amifostine in broilers currently available. It includes and stores the product. Furthermore it; Hospitals without JB stocking special packaging and significant costs in eg Ju Freeze would be unable to supply amifostine for use with their patients (although

Cua (Third world markets will be comprehensively inhibited from the use of amifostine). However, there were no alternative formulations available; 10 clinical trials have been carried out using this formulation. To develop a dosage form that is stable enough to provide a long shelf life at room temperature or under less intense refrigeration; Which is not exclusive to many drug products.

And z village. The invention Jal describes novel, state-of-the-art procedures that produce solid formulations containing an E!

Powder-dried amifostine & with or without Las an acceptable catch wy as mannitol:

Which have an improved stability over the pre-existing formula. General description of the invention o The present invention relates to a process for preparing crystalline compositions which includes the following steps:

aminoalkyl alkyl dihydrogen phosphorothioate gid Prepare a composition comprising 1° or compounds RHN(CH,),NH(CH;)mSPO3H; having the formula dihydrogen phosphorothioate being the 11- or alkyl R-hydrates thereof or salts of the alkali metals; in which B and a solvent solution are 1 (BY -©). « and © may be independently an integer of

Ve is alcohol and water and contains relative amounts of alkyl amino dihydrogen phosphorothioates; alcohol and water so that a solution free of particles is obtained at ia a temperature ranging from about room temperature to about 10°C; which also provides a crystalline precipitate of alkyl amino dihydrogen phosphorothioate upon cooling below fp Ja and

LY ae _cooling the composition to a temperature below zero degrees for a period of time sufficient to cause the precipitation of crystalline alkyl amino dihydrogen phosphorothioate; And

LY Vacuum drying of the resulting mixture to leave a solid crystalline preparation which has enhanced temperature stability. step Lilia) of the present invention; Sterile inert gas Jie argon, nitrogen and helium can be inserted over the preparation.

a

preferably The temperature to which the composition is cooled to start the precipitation of crystalline alkyl amino dihydrogen phosphorothioate in the Ahi range is 016006 minimum for melting

combination. ideally; The formulation may also contain formulations such as mannitol. The alkyl amino dihydrogen compounds include aminoalkyl dihydrogen phosphorothioates © suitable for use in the present invention but are not limited to (ie sud -©( -7 -propylamino) ethyl dihydrogen phosphorothioates (amifostine) 1 S-2-(3-aminopropylamino)ethyl dihydrogen phosphorothioate (amifostine) and 5-=Y (©-methylaminopropylamino)ethyl dihydrogen phosphorothioate (WR-2689) ¢S-2 (3-methylaminopropylamino)ethyl dihydrogen phosphorothioate (WR-3689) & JAY) - 7-5 0-aminopropylamino)SD ethyl hydrogen phosphorothioate S-2-(3-ethylaminopropylamino)ethyl dihydrogen phosphorothioate « f =v) Y-S (aminopropylamino) -7- methylpropyl dihydrogen phosphorothioate §-2-(3-aminopropylamino)-2-methylpropyl dihydrogen phosphorothioate « and 5- -Y (7-amino) ethylamino)- ?- ethyl chiral hydrogen phosphorothioate d 5¢S-2-(2-aminoethylamino)-2-ethyl - dihydrogen phosphorothioate 58 - 7-(4-aminobutylamino)- ?- ethyl SB hydrogen phosphorothioate S-2-(4-aminobutylamino)-2-ethyl dihydrogen phosphorothioate ¢ and 5-=Y )° = aminopentacyl amino)-? (5-aminopentylamino)-2-ethyl dihydrogen phosphorothioate and 5 - Y = (1-©aminohexylamito)-?-ethyl dihydrogen phosphorothioate S-2-(6-aminohexylamino)-2-ethyl dihydrogen phosphorothioate « and 5-?- ) a! EV) | :

VI

Amio)- ?- ethyl charic hydrogen phosphorothioate J methylamino phosphorothioate = v) -¥ -5 f ¢ S-2-(2-methylaminoethylamino)-2-ethyl dihydrogen phosphorothioate

S-3-(3- (WR-151327) propyl dihydrogen phosphorothioate {sd methylaminopropylamino in .methylaminopropylamino)-3-propyl dihydrogen phosphorothioate (WR-151327) god phosphorothioate AD preferred embodiment © « WR151327 5 WR3689 Amifostine is an aminoalkyl dihydrogen phosphorothioate and most preferred amifostine. Suitable alcohols for alkyl amino crystallization include dihydrogen phosphorothioate for use in the present process; But it is not limited to propanol, ethanol, ethanol, methanol, Michael Ja JS alcohols, 0,0- and sec-butanol sk — 5 n-butanol and p-butanol isopropanol and isopropatol 0 and its cognate 2-pentanol —Y-pentanol and n-pentanol —“ tert-butanol and preferably ethanol. eld in a special process of the invention; The temperature of the mixture produced in step (b) is raised to the solidification temperature which is about 1 °C to about 10 °C above the lower melting temperature of the formulation; followed by cooling the temperature of the mixture from the solidification temperature once more ve fy Lill pill to the minimum melting temperature or less before drying in the eutectic range (C). In specific cases; the temperature may fall The minimum melting point (uotic) ranges from about -860 C to about zero degrees; while the solidification temperature may lie in the range of 10 C to about -70 C.

A: - With that; It is an object of the invention to provide a process in which the composition includes about *0 mg to about 4060 mg aminoalkyl dihydrogen phosphorothioate per milliliter of composition; z and about 71 to 170 (based on volume) alcohol; And about 115 to 144 (based on volume) water. preferably The formulation includes approximately 171 mg to about You mg alkyl amino dihydrogen phosphorothioates per milliliter of formulation; about 8 to 1710 (by volume) alcohol; and about 7800 to 795 (based on volume) water. The most Spicy formulation includes about 100 mg alkyl amino dihydrogen phosphorothioate per milliliter of formulation, about 701 (by volume) alcohol and about 7960 (by volume) water.

0 The temperatures of the different vacuum cooling and drying steps can vary widely depending on the specific ratios of amino dihydrogen phosphorothioate to alcohol to water. Generally; 0 anyway; The temperatures for steps (b) and (c) lie in a range of about fom m to about ©m; Preferably around -1 mm.

| In a specific embodiment of the present invention; The process includes a sterilization step. Sterilization may be induced (ly number

1 A method well known to these persons of skill in the yard is as heating the mixture in an autoclave”; or treatment with gamma irradiation, Adina recrystallization, or sterile filtration solution; For example” through a filter with a pore size of 157 micrometers. Note must be made; Furthermore it; It may be an alkyl amino dihydrogen phosphorothioate crystalline anhydrous or solvent-containing crystallization. particulary; Oral amifostine may be anhydrous; or solution; or hydrate; like

59/11 z

monohydrate or dihydrate. In general the hydrate compounds may contain about 1 to about ©' and preferably about 1 to about 7 molecules of crystal water. in an alternative procedure for preparing the formulation; The amino alkyl dihydrogen phosphorous is soluble in thetiboate.; such as amifostine 0 and any desired formulations in water for injection; USP and the resulting 0 solution is then sterile filtered. after that; The required amount of sterile alcohol such as sterile ethanol is added to the production of the composition that Jl is subjected to the cooling or hardening steps. In addition, the composition produced according to the exposed process may include a pharmaceutically acceptable excipient. Matching wording included; But it is not limited to sodium chloride “or propylene glycol” or sucrose “or dextrose + or sorbitol Jom jem Ve “or inositol” or mannitol J sue » or glycine ¢ or arginine ¢ or cs 3) amino acids and preferably mannitol and most preferably mannitol » NF cells, a special objective of the present invention is to provide a process for the preparation of a pharmaceutical composition containing on crystalline amifostine which includes the following steps: ( ) prepare a composition comprising about 100 mg to about 100 mg amifostine per milliliter of composition; about 77 to about 770 (by volume) ethanol; and about 170 to 797 (by volume) water; optionally; about 0 composition so that a particle-free solution is obtained at temperatures ranging from about room temperature to about 10 °C, but which also provides a crystalline precipitate of amifostine On cooling less than Cool the composition to a temperature which lies in the range of about -40 °C to (Y) about -40 °C for a period of time sufficient to cause the precipitation of crystalline amifostine; and vacuum drying of the resulting mixture to leave a solid crystalline amifostine preparation which (7) °: has an enhanced temperature stability. In general, the steps taken after step (a) and before step (c) are carried out over a period of time an hour. YE is done an hour; And favorite about? 1 hour to approx VY 0 + hr to approx Execute those manipulations taken in step (c) over a period of about 1 hour to approx. plus 70 hours to about 10 and preferably about dela VY about 0 mTorr 01 mTorr that; The vacuum drying of step (c) is carried out in a vacuum of about 151 mT and preferably 0001 to about 151 mT of the present invention by preparing a sterile pharmaceutical composition having a Lad stability relative to another objective. Active Ingredient © ie; Alkyl Amino Dihydrogen Phosphorus Led heat enhancer in which it remains at above 4m for at least two years. And in the form of Bl netsofima crystallized theoate like ve in lh is preferred; The amino alkyl dihydrogen phosphorothioate remains crystalline; As amifostine; about ambient temperature for at least two years. Accordingly, a compressed formula is provided; sae) with enhanced temperature stability as the formulation includes crystalline amifostine which can be formed with a pharmaceutically acceptable carrier into a particle-free injectable drug product. Preferably; the sterile formulation is supplied as a sterile single-dose formulation with enhanced temperature stability that includes

- 11 - about 0.1 mg to about 000001 mg amifostine crystalline and optionally; about 10 milligrams to about 00001 milligrams of a pharmaceutically acceptable formulation; The formulation may be reconstituted with a pharmaceutically acceptable carrier into a particle-free injectable drug product. in a more favorable embodiment; The sterile single-dose formulation includes about 100 mg to 1,000 mg Jao crystalline amifostine and about 100 mg to about 1,000 mg formulated formulation. the most favourable; The composition contains about 8010 mg crystalline amifostine and about a gram of mannitol. The carrier may be selected from a wide variety of pharmaceutically acceptable carriers and may include water for injection; (USP) and USP "sue" or dextrose saline solution

.aqueous pH buffers ol or USP buffers

0 An additional objective of the present invention includes a method for treating a patient in need of radiological and chemical protection; Which includes giving the patient a quantity of a pharmaceutical formulation containing crystalline alkyl aminodihydrogen phosphorothioate having the general chemical formula described by such as amifostine; which has been reconstituted with a pharmaceutically acceptable carrier. The reconstituted pharmaceutical composition may be administered by non-enteric route. as you like; combination may be given

1_ Reconstituted intravenous pharmaceutical; and in the muscle; and under the skin 6 and within the phage; and inside the bag. These and other aims of the invention shall be clear to a person of ordinary skill in the art from reading the general and detailed description provided herein.

Brief description of the graphics:

Figure 1: A graph of the solubility of amifostine (WR-2721) in aqueous/Y ethanol solutions against temperature.

1117 - z Figure ?: A graph of the dependence of the solubility of amifostine on the concentration of ethanol. The TGA oF form of a crystalline drug product amifostine JS from 701 ethanol in water. Form: TGA of amifostine. Figure #: DSC of a crystalline drug product amifostine formed from Jl 01 in water. M form +: DSC of the drug amifostine. Figure 7: FTIR of lie product amifostine JS from 101 ethanol in water. The FTIR GA form of the drug amphivocetine. Figure 4: X-ray diffraction of a crystalline drug product amifostine formed from 701 ethanol in water. Figure 01: X-ray diffraction of amifostine. z 0 form TGA $V) of crystalline amifostine and the drug mannitol J is produced from 10 ethanol in water. Figure DSC VY of crystalline amifostene and mannitol JS product from 10 ethanol in water. ENF FEES NEEL FICHE form of dried amifostine in broilers. Detailed Description | SAM prior to the present invention; The available pharmaceutical formulation of amifostine (Elhyol®) was not thermally stable. Due to the instability of culls, the Elhyol® formula requires the use of low temperatures during transportation and storage in order to prevent product degradation.

- 1 -

The present invention provides the first combination; Pharmaceutical fixed vacuum dried of amifostine which can

be properly handled and stored at temperatures of; m to about a temperature

room for extended periods of time without significant decomposition of the product; Accordingly, it provides a solution to a long need

Find it. The formulation will allow the amifostine product to be transported and stored in hospitals around Alam 0 that do not have the cryogenic storage capabilities required for the existing formulation la

unexpectedly It has been discovered that the sterile, stable product of amifostine crystalline with or without

Formulation(s) such as mannitol may be prepared from vacuum drying of an ethanolic solution

Aqueous containing Ge sale amifostine in an amount of about 1/ to about 75 ethanol.

An important feature of the present invention included preforming studies which determined:

daly (V) 0 substance amifostine (mg/ml) in different water/ethanol concentrations.”

And

(7)_ The solubility of amifostine in water/ethanol at different temperatures;

(©) The suitable storage temperature of the freeze dryer required to induce precipitation of amifostine prior to drying in vacuum 0 and

\o) ¢ the concentration of ethanol required in the formulation to yield a highly saturated solution which causes; when cooled to desired storage temperature in a freeze dryer; in the precipitation of amifostine in crystalline form. and from the preformation studies above (see the following examples); It was determined that it was the preferred concentration of amifostine; on an anhydrous basis; about 1001 mg/mL

59/1

= - 16 liters in about 1) aqueous ethanol. Furthermore it; A preferred storage temperature of about yom C will induce precipitation of amifostine. In order to obtain an excellent solid AES product, the percentage of ethanol in the ethanol/water mixture ranges from about 71 to about 779 on an ethanol by volume basis (eg; ratio 0 ethanol:water:1 94 5© : 15); likewise; The Freezing Canal storage temperature can range from about 0°C to about -01°C; Preferably ga Vem, the results of preforming studies represented in this invention are an important basis for adjusting the interdependent variables of amifostine concentration, ethanol concentration, and temperature to provide multiple container size/fill volume combinations.

0 Generally a freeze dryer rack is precooled to a temperature of about Tom 0 C to about cp Vom and preferably about Yom C. The vials are filled and the temperature is reset to about Yom C and to about Vom C. preferably Yom C. The vials are maintained at this temperature for about Yo hours. depending on the concentration of ethanol, amifostine or amifostine formulated in solutions; Depending on the concentration of JANI, the degree of JANI will change

1 | _ the temperature necessary to cause sedimentation accordingly. The precipitation of the cryopreserved amifostine then occurs, followed by immobilization of the formulation once solidification of the formulation has been observed; The main drying cycle is started to remove excess water and ethanol. As dale the pressure in the chamber is reduced to about 101 mtorres. The main drying cycle is completed when the Yom formula temperature is approximately +7°C for more than 2 items. © During the secondary drying process; The composition is maintained at about Yom to about 10 m;

m z and preferably at a temperature higher than the main drying cycle temperature; for about 40 hours to about 0 5 hours to facilitate secondary drying; No removal of water and residual ethanol. When the partial pressures of water and ethanol in the chamber reach Alla is stable; It is considered done: Drying completed. These formulations provide a vacuum dried product which has been found to be '0' crystalline amifostine which exhibits plik stability over the current formulation which contains amorphous amifostine. Bae vials can be stored and reduced at temperatures of about ; C to about Z room temperature without significant product degradation. Furthermore it; Formulations may be added to increase the amount of solids in the formulation. Among the formulations found useful for this purpose, often in combination, are 0 sodium or potassium phosphate, sodium chloride, citric acid, tartaric acid, gelatin, and carbohydrates such as 0-dextrose, sucrose, sorbitol, inositol, mannitol, and dextran. dextran In addition to those referred to herein in this patent other formulations are known by these persons skilled in the art. z ve The vacuum-dried crystalline amifostine solids of the present invention may be supplied in single-dose container forms by aseptically filling suitable containers with the previously vacuum-dried sterile solution to a indicated amifostine content and preparing the desired vacuum-dried solid formulation; Then seal the single-dose container tightly. It is intended that these filled containers will allow rapid dissolution of the solid formulation upon reconstitution with appropriate sterile Y-diluents in place which yields an appropriate sterile solution of the desired concentration of amifostine for administration. the expression “lie containers” as used herein; Preserving container

es z on a sterile environment; like a bottle Capable of delivering vacuum-dried product well sealed by means of a seal. In addition; Suitable containers include fit-to-size; Z, considering the volume of the solution to be kept when reconstituting the dried composition in vacuum; suitability of container length; As le glass of the first type. It must be understood that the bridging method used is; These include, for example, sterile rubber stoppers or equivalent; Those providing the tightness indicated by Jd: but which allow Lad entry for the purpose of introducing the diluent; for example, USP sterile water for injection, USP saline solution (soe), or ye dextrose in water “ (USP) to reconstitute the desired amifostine solution. These and other features of suitability of containers for pharmaceutical products such as those of the present invention are well known to persons skilled in the practice of the pharmaceutical arts. While physical properties such as appearance have been improved in present solid formulations; Which thus achieves one of the objectives of the invention, we unexpectedly found that these current solid formulations have improved thermal stability compared to the currently known formulation. Stability of the solution form of the pharmaceutical composition. In contrast to eel, the present formulations exhibit enhanced chemical stability between solid dosage forms; see the following examples. The pharmaceutical formulations of the present invention are suitable for administration by non-enterial route, eg (JB) intravenous infusions; and in muscle + and in the cavity; and inside the sheath; and under the skin. vo The following examples are intended to be illustrative of the present invention and should not be construed in any way; to be his identification.

aad Example No. 1: Procedure for formatting (formation) studies This provides example 1 for a procedure. used for preformulation studies that were then designed to assess appropriate factors; i.e., amifostine concentration, ethanol concentration, and temperature; To obtain a sterile, vacuum-dried 0 form of crystalline amifostine with or without pharmaceutically acceptable formulations using vacuum drying of a water/ethanol mixture a. Prepare sample solutions in separate test tubes with screw caps add the following: : 906 μl cla 0 75 800 µl You sla 1 µl ethanol ton water 9060 µl ethanol 0 µl water 1 5 µl ethanol tees 1 µl water 1000 µl ethanol Add amifostine to each test tube until the solid remains intact melted. Jam I voted Ye sad ve a second. if all amifostine has been dissolved; Add an additional amount of the drug until the particles remain insoluble in the solvent. Shake the test tubes vigorously for 1 min Fe at yo °C.

1 A - — _ B - Prepare standard solutions Prepare 10 ml of the following solutions of drug substance in mg/ml water and 01 mg/ml water. 0 Vv o mg/mL 5 mg/mL on a Violet Gas Spectrophotometer ' Measure each solution against waste water over a range of 5 agli 79.0 — + note (record) the absorption at 001 nm or 01 nm. Perform a linear backscatter analysis of standardized data at Yoo nm or 701 nm and obtain 0 slope and intercept value. C- Analysis of sample solutions Remove approximately 1.6 milliliters from each solution and centrifuge into granular solids. Filter each sample with a 1.45 µm filter to remove excess particles as necessary. Dilute each sample to a working concentration of 0 mg/mL to ¢ * mg/mL with water. on the UV spectrum; Scan each sample over a range of 0,910 nm to 740 nm: Obtain a reading for each sample at 0,010 nm or 701 nm. of standard inclinations, intersections and dilutions; Calculate the concentration of amifostine in each solution. Cool the solutions to the next lower temperature and repeat the previous one after it has been desired

—- 9 a b at a temperature of one el duration. Table 1 provides the results of a ub courses of amifostine in . Ethanol/water mixtures at different temperatures. This relationship is illustrated graphically in Figures 1 and 7. Table, 1 Mean solubility of amifostine trihydrate in ethanol/water mixtures (mg/ml) [ee [foe] © This example shows that the solubility of amifostine trihydrate in ethanol/water mixtures (mg/ml) [ee [foe] Substance amifostine be strongly dependent on all of the content

The common solvent is ethanol and temp. In general, the degree of high saturation resulting from a drop in temperature of the amifostine solution decreases with the increase in the content of the co-solvent ethanol (refer to Table No. 1 and Figures 1 and 1). This dependence is exploited in the two examples No. ? and the following © figure for a crystalline amifostine probe.

Z Z 067 Example No.? : method for producing crystalline amifostine without mannitol: add (YY, TO) gryhydrate of amifostine; which is equivalent to (IV) grams) of amifostine anhydrous. Stirring into 1” (1 milliliter) water at 75°C. Z after complete dissolution of amifostine; (VV) mL) absolute ethanol is added; USP to 0 solution with stirring. Water is then added to (0.711mL) 05. The resulting solution is sterile filtered through a 1.77 µm filter. ml of the filtered solution is dispensed into each of the thirty-three 01-ml vials to give 900 mg amifostine on an anhydrous basis; Each vial has an ethanol:water ratio of 10:40. Slotted stoppers are placed on the vials and the samples are subjected to the following vacuum drying cycle: the samples are placed on the 0 racks of the freeze dryer; Which has been pre-cooled to about Zom C for a period of about 17 hours at ambient air pressure, where after this time the chamber is emptied and the shelves are maintained at about Zm 7 C for a period of YA hours. after this period; The chamber is filled a second time with nitrogen and the bottles are quickly closed by hand. This procedure results in a thermostable lyophilized single-dose vial containing approximately 1g (eo) of crystalline amifostine as a solid 10 premium shell. Example No. *: A method for producing crystalline amifostine in which approximately 71 (grams) mannitol is added with stirring to (aro) water at 10 °C. To this solution is added; stirred” (YO) g) sala amifostine (trihydrate base); Z, which is equivalent to 71 (grams) of the substance lie anhydrous amifostine. after complete dissolution; 71 (©71 mL) ethanol USP “ALY” is added volumetric to the solution with stirring. EV water is added

YY - | - 8 to 100 ml): The resulting solution is sterile filtered through a 107 µm filter and ©ml of the solution is transferred into each of the 40 10 ml vials. Slotted stoppers are placed on the vials and samples are packed on a lyophilized rack at ambient temperatures. The shelf temperature is reduced at a rate of ¥ m/min to yom m and maintained at this temperature for 0 min to initiate crystallization of amifostine. after this time; The shelf temperature is raised above the eutectic degree at a rate of 7 m/min to oom and maintained at this temperature for 10 hours to harden the product. after that; Decrease shelf temperature to -Yo C until product temperature is OF a) A= for more than 10 minutes. after this time; The freeze dryer condenser is turned on and the vacuum from the chamber is reduced to 101 mtorres. The rack temperature is raised to 0 °C and samples are allowed to dry in vacuum for 06 hours. at this point; Continued vials are reached at rack temperature which indicates the end of the main drying cycle. Vials of Aida Vo Milli-Tour remain on the shelf at Yom temperature 17.4°C for an additional 17.4 count to ensure that the water is removed non-hydrate. The chamber is again filled with nitrogen and the vials are closed mechanically. This procedure results in a thermostable lyophilized single-dose vial of 0 containing ©001(mg) amifostine (anhydrous base) and (©+©mg) mannitol as a premium hard shell. Example No.: Stability test of crystalline amifostine dried in vacuum Several airtight vials filled with nitrogen are strained from crystallized amifostine plas of 0:00 ethanol: water as shown in Example No. "del" at __C for a period up to Vo days © A to determine the thermal stability of crystalline amifostine.

YX Y -— _ results are tabulated in a number table? below. All data is reported as a percentage (7) of the initial concentration, which is designated as 7001. Table 1 Time at 90 m (days) dl Interval of initial concentration AA S S S S N A A la aa we IE I ee ee oe Cee For comparison purposes, the present amorphous amifostine formulation is also subjected to a stress test

m at 0°C for up to YA days. The results are represented in Table No. ? below. All data is denatured as a percentage (7) of the initial concentration which is designated as Vee A

Y Y _ _ . Table No. © Study a at 00 m (in days) | Percentage Ratio of Initial Concentration (7) oT oe eee ew ee pe oe oe | ell It is abundantly clear that even among solid formulations a drastic increase in stability is achieved Thermal by crystalline compositions obtained from the disclosed process EXAMPLE 0: A PREFERRED METHOD FOR PRODUCTION OF CRYSTALIC AMIFOSTINE 0 Procedure for a lambhostin/mannitol 001 formulation (anhydrous mg each/mL) The following procedure is written to produce ©5, L of solution.<1 00 gram mannitol (USP) was dissolved with stirring (a magnetic Teflon stir bar) in about 70 mL pure water to nanopure at room temperature in a pressure vessel Made of stainless steel 9/11:

Y $ _ — = 74.7 added; gram amifostine trihydrate to this solution. The dissolution was aided by vigorous stirring. #»-_ after complete dissolution of amifostine; mL dehydrated ethanol (USP) was slowly added to the solution with vigorous stirring. Precipitation of amifostine at the o-addition site followed by rapid re-dissolution occurs when the ethanol is diluted by stirring. - After completing the addition of ethanol; The solution was diluted to 790000 mL with purified water to da nanoparticles. 5- Then the solution was filtered under a positive pressure estimated at 01 pounds per square inch (nitrogen) through a Millipore-40 filter 1 - © milliliter of the resulting solution was transferred to each 01 liter vial of 101 Vials (Wheaton E-2910-B47B) Vials were partially sealed with gray butyl rubber stoppers (Tompkins 012380857 F2) and vacuum dried. Vacuum drying cycle of amifostine/mannitol 001 (anhydrous mg/ml) 1. Vials are placed on the rack at approximately yo m; To ensure that the precipitation of Vo amifostine is not initiated heterogeneously. 7- The shelf temperature is reduced at a rate of 7 m/min to - © 0. A v Once this shelf temperature has been obtained; It is kept stationary for 70 minutes

Yo — - to ensure that the solution is frozen for all vials. during this stage; Samples pass through utensils (approximately V1). | º *- At the end of the 1710 minutes of memorization time; The rack temperature is raised at a rate of 7 m/min to zero over YO min. Once this temperature ° has been obtained; Boiling is kept constant for 10,000 minutes. . ¢- At the end of the Teo min keeping time ya 5 sec the shelf temperature is reduced to Ton m at a rate of 7 m per minute. Once this temperature has been obtained it is kept constant for VAY minutes. ae -0 This time the capacitor is on. When the condenser temperature is below - 1 0 C the chamber is emptied. when the room pressure is less than 1010 mTorr; The rack temperature is raised to Yom d m at a rate of 7 m per minute and the chamber pressure is maintained at 150 mT as the chamber nitrogen is discharged. >- The product is left in the room at 151 mTor for 11 to YE hours after the temperature of the processed product reaches the shelf temperature. uly 2 ya a Filling \o the chamber with nitrogen and closing the vials 0 Note: 1 Torr is equivalent to 1 mm Hg at zero degrees. Airtight, nitrogen-filled 01-ml tube vials containing dried crystalline amifostine were strained in vacuum; Then obtain it as described in Example No. © ¢ at the degree of a ge. for a period of time; weeks. For crystalline amifostine dried at 11 °C sad a yom hour; 197 remain

of amifostine at the end of the stress test period. For crystalline amifostine dried at -LY for dela YE 784 amifostine remains at the end of the stress test period. J No. 1: Most preferred method for producing crystalline amifostine The most stable vacuum dehydrated crystalline amifostine was obtained by Coin) in a vacuum of an amifostine/mannitol solution; Ve-containing ethanol/water is based on ethanol. The procedure for the compound is the same as described in Example © except for a smaller amount of dehydrated ethanol added to the solution. The specific method of implementing the drying cycle in vacuum to produce the most stable crystalline amifostine was reached after several studies were conducted to evaluate the effects of changing the final drying temperature; and 0 time to final drying and initial cooling rate to Yom m for the vials containing the solution. It was found that, in general, the stability of crystalline amifostine was greatest when the final drying temperature was at Yom C; The final drying time was between 11 and 4? hour. Moreover; The stability of crystalline amifostine was higher when pre-cooling to Yom of the vials containing the solution was performed in 101 min instead of £0 min. 1 Based on previous development studies; The most preferred method for carrying out the vacuum drying cycle is as follows: Vacuum drying cycle of amifostine/mannitol (01 mg/mL anhydrous) Vials are placed on the rack at approximately a Yo to ensure that no Precipitation of amifostine is initiated heterogeneously.

TV - : - "- Shelf temperature is reduced from YO .m to zero in Te min; from zero to 01 ia Ye min; then from 1- 7°C to Tom in min 80 min.Once this rack temperature has been obtained it is maintained constant for a period of Yee min to ensure solution solidification of all vials.During this dda pall the samples pass through a 9 otic (ip VI) VY at the end of The Yeo Minute of holding time; the rack temperature is raised to zero over the YO min. Once the rack temperature has been obtained, it is held constant for 10 minutes. - At the end of the Tes Minute of time Jada The temperature of the rack is again reduced from 10°F to Vo°C in 1 minute and then from -91°C to Vo°C in 101 minutes. A heat of a Yom is kept constant for a period of YA. min. 0 After this time the condenser turns on. When the condenser temperature is less than -0 |m the room is emptied. When the room pressure is less than , 1510 mTorr The shelf temperature is raised to -To C and to Yom C at a rate of 7 m per minute while the chamber pressure is maintained at 10 mT with room nitrogen discharge. 1 The product in the vials is then left in the room at 1510 mTor for 11 to YE hours after the temperature of the processed product has been seamed to shelf temperature. Once again, the chamber is filled with nitrogen and the bottles are closed.

: | -78- Note: 1 ox is equivalent to 1 milliazard at ian zero m | without wanting to adhere to theory; It is believed that step (7) above causes nucleation of amifostine crystals in the freezing solution and step (©) causes the growth of amifostine crystals around the nucleated crystals and ensures partial completion of amifostine crystallization from the frozen solution. Crystalline amifostine was produced by using the drying cycle in vacuum wel and using 717.9 ethanol-solution produced by the final drying step of YE hour. A stress test of these two products at 0°C for eight weeks showed no degradation of amifostine for the product dried for VY hours and a degradation of 7/ to amifostine for the product dried for VY hours; 7 hours. Example No. »: Preferred Method for Executing the Stability Test of Crystalline Amifostine 0 Strain vials in the form of sealed nitrogen-filled tubes of 01 mL containing crystalline amifostine dried in vacuum; obtained as described in Example No. 36; At 550 °C up to eight weeks. It was found that the previous stability test at +0°C caused the decomposition of crystalline amifostine in sealed vials in a manner not readily associated with the stability of crystalline amifostine under typical storage conditions of 1 (ie at a cooling temperature of about 1°C). However, the stability test results at a score >a and lower can be correlated with the stability of crystalline amifostine under typical storage conditions. As an approximation; Persistence of one month at degree Ye C corresponds to eighteen months at degree 4; Stability for -7 weeks at 40°C corresponds to VA 1 month at Cat° and stability for -8 VY weeks at 460°C corresponds to VA 1 month at 5°C. 59/1

Y 3 — © _ See Lachman et al. 1. Theory and Method of Practicing Industrial Pharmacy ¢ pages VIV=Y11 for the general study of predicting stability. at the end of the stress period; Crystalline amifostine in vials was tested for water content determination; And thiol content, and amifostine content. The water content was determined by Karl Fischer titration. Since amifostine may hydrolyse under stress to yield 7-[(*-sudpropyl)amino]ethane thiol and phosphoric acid, the determination of the amount of this Thiols give an indication of the stability of amifostine. The analysis of water content and thiol content was carried out using the following procedure: 1- Preparation of standard materials and samples. 0 Weights and volumes are adjusted provided that the final concentrations remain the same. Solutions are stored under refrigeration and/or in a refrigerated autosampler immediately after preparation. 1-1 Prepare standard solutions of amifostine (7 mg/mL); Methanol/1[ele 0/5 5]) Weigh to an accuracy of about 050 mg standard amifostine in a 10 mL standard flask. Dissolve it in ml ela and reduce to volume by methanol. ve Storage period YE 1 h at 4 C. 7-1 Prepare a standard solution of =F [(3”-aminopropyl)amino]ethane (Jad dihydrochloride “71”). mg/mL free base; methanol/water 1 0 M (le 0 i | 9/1

- .2M weighed with precision about 1,825 mg of 7-(=F)aminopropyl)amino]ethanethiol; dihydrochloride standardized in a 100 mL meter flask. Add 090 mL of water and then dilute to volume with methanol. Storage period: 4 hours at 4 pm. 0 1-? Preparation of amifostine (drug substance) a- Preparation of the experimental sample.(7 mg/ml; methanol/water [0 0/5 5]). Accurately weigh approximately 0.550" mg of amifostine in a 10 mL standard flask. Dissolve it in ½ mL water and dilute to volume with methanol. Storage period: a oye dela YE 0 a b - related material (V0) mg/(sla ca.) Weigh with an accuracy of about 150050 mg amifostine in a 10mL calibration flask. Dissolve it to volume with water. Storage period dela YE at -6m1; preparation of amifostine for injection ( drug product (caf puma £,A) methanol/water 1[ 0/5 5] vo Dissolve the contents of the drug product vial in about 4 ml of water.

S Quantitatively transfer the sample into a Y0 mL metering flask Cody to volume with water. Transfer 7 mL of this mixture to a 50-mL measuring flask; Add 14 mL of water and dilute to volume with methanol. Storage period: dela YE at 4 m. M ?- Adaptation of the regimen —- amifostine (Use standard solution contained in (V2) RSD 7 for six repeated injections of amifostine > Y Delay coefficient > Y z Number of theoretical dishes > Youu ee 0 7< [(©-aminopropyl)amino]ethane “Jad Dichloride (WR-1065) (Use standard solution −dl in (Y=) RSD for 6 injections 0 << Delay coefficient z 2 Y : number of theoretical dishes z > mrola 1 7”-_ equipment and materials (as mentioned later or equivalent) z

Q: Equipment HPLC system with ultraviolet (UV) detector Material: Amifostine Standard 0 Phosphoric Acid Concentrated: 5 HPLC 4c

HPLC des : (MeOH) methanol Purified water : 11 megohm or greater The sodium salt of 4-octanesulfonic acid (L 251): HPLC quality HPLC HPLC conditions z 0 Column specifications: Filling material: Haas TSK ODS-80TM « Coated at both ends (USPLI) Dimensions: £7 x .mm Particle size: © µm. Mobile phase: re phosphoric le pH 7.00 32.59 mM d OSA (0/04)

AA

FACT -(1) 088 g in 501 mL aqueous phosphoric acid pH 7.0 0001 Jia (Y) mL by methanol. (©) Filter and degas from the mobile phase. Disclosure: YY. Absorbance nm m Flow rate: 0.1 mL/min 01: Gall aaa µl Column temperature: room temperature Sample temperature: 40 m Inhibition: Adjust until it yields about 780 full-size amifostine peaks .

:(;)_Procedure 0-0 Inject the sample and standard solutions; Record the amifostine peak retention time (approximately ; minutes). To confirm the identification of amifostine 01, the peak retention time of standard amifostine must be within

present in the sample. .. (9) Calculations 0 Amifostine Experiment i Amifostine (1 w/w) = $V) i

Y § _ _ Sample Area Weight of Standard (mg) Yoo XP X x Area of Standard Sample Weight (mg) + 7 Purity of Standard = p —_ vu 3 Amifostine Trial for Injection 7 Lamifostine (No Aqueous) labeled = Sample Area Weight of Standard (mg) FXPX — x o_o ° Area of Standard Ja 0 (1#mL) (Jav2) Yoo X = F = Lean , 1 ¢ (da) )+ + ©mg/vial) WR-1065 WR-1065 7, in amifostine = area of WR-1065 ─ standard weight of WR-1065 (mg) 71ppssssssss XFxpx 0000 X Area 1718-1065 ld Weight of Amifostine (mg) A & 0 ml = F Ada 1 01.2... Xx Ja 1 01

YT o —_ WR-1065 7 in Amifostine for Injection = Area of WR-1065 Sample Weight of Standard WR-1065 (mg) m MSD XFXP XK —_ Area of WR-1065 Standard 0 Fill in (dee) (deo) Yy2W=Veo x =F 1 0( I Cal *mg/vial) Related Substances RS)(RS) 0 Eliminate peaks on the chromatographic curve For a sample of the relevant material that is found on a curve. Matter free from related matter or peaks arising from perturbations of the solvent introduction. For each additional related material detected Jal 0 Relative apex area percentage: The crest area (RS) of each individual related material = SS 0.1.” A Total Jala peak area percentage of item 178 -1065 and any other additional related material greater than 70.1 sq. 01 area. Ja Total related articles. Example A: Stability results of crystalline amifostine dried under vacuum and subjected to stress at 40 °C. The typical results obtained from the strain pathogenic product amifostine by the pelleting method are summarized in Example No. + for the strain tested according to Example 101. No. No in Table A) $V | i

- “> 7 _ Table (3) results of the stability of crystalline amifostine dried under vacuum at tr m time 7 ela standard 7 thiol amifostine Acceptance | NEY w/w not exceeding (NMT) 77 | 147-78 w/w w/w w/w of el wl am ava NMT not exceeding (not more than) the foregoing results clearly demonstrate the enhanced stability of crystalline amifostine produced by the method described in Example 6. The enhanced stability is evident from the lower percentage by weight of thiol formation which shows a very slight degradation of amifostine by hydrolysis to be 7-(=F)aminopropyl)amino]ethanethiol. In addition, there is a small loss of water content or amifostine content with time; This contrasts with the low stability of the amorphous and vacuum-dried amifostine formulation, which showed significant degradation within VE day at 00 C (see Table (©) in Example No. (4). i 9/1

- Bg pu Example No. 4: The crystal structure of vacuum-dried amifostine. The molecular structure and crystal structure of crystalline vacuum-dried amifostine have been determined. The cell unit was determined; Collecting data using copper radiation at Ssh, conducting a room temperature survey. All atoms different from hydrogen using different azeotropes. The position of the hydrogen atoms attached to the nitrogen atoms and the oxygen atoms present in the water was determined from Fourier variation curves and called La nS azeotropy. The positions of the remaining hydrogen atoms were calculated assuming ideal geometric positions. It was not refined. These hydrogen atoms due to the low inversion of the variable ratio 01 The compound crystallizes in the large space group to A0 The data shown in this example are from and m8 = 47 0+ (other isoforms +o TT = 8) the isoform with values 8 Least clarified molecular structure and imagined crystal structure POLARS have values of 18 < 047 and Ba[‎

OF) Drawing of Lamiphosthene Trihydrate dried under vacuum in the form of Experimental work: \o Data collection: A needle-shaped, flat, colorless crystal of 0.11:::0005 has approximate glassy dimensions. All measurements were made on a diffractometer aad b, “mm at 7” Xo”, ©. X 0 , Y Qe 69/11 i

YA — _ Rigaku AFCSR monochromatic CuKa radiation powered by graphite and 0.38 kW rotary anode generator. The cell apt and directional matrix 7 were obtained to aggregate the data from refining by the least squares using adjustment angles of 710 which carefully focus the reflections in the range OFF 0 > 07 > 445 corresponding to a cell in the form of a straight rhombus (Sa) H A(T) Ato ’ A (Y) 7,507 - 8 p < -khdlar A (Y) 7 < 0.1 (m) d : 0 when A = Z ; And YIAYT = FW, the calculated density is 0.447 g/cm. based on inconsistency. nY #h : h0O k : 0kO # tha on #1:001 1 and the successful solution and refining of the composition; The spatial group has been identified as: 1 ( No. (V8 69/11 0 )

_ 3 ga _ Data were collected at a temperature of +1 YY C using a 28-© scan method. Even a BY value of VY oe omega smears have multiple strong reflections; in place prior to data collection; It had an average width at mid-height of 0.71 with a departure angle of 6.0. Smears of 1.04 + 1.84 (0 x) were made at a speed of 8.0/min (in omega). Weak © reflections (> (oD -15,-) (with a limit of ad; sale] scans were re-scanned and CIS compiled to ensure the quality of the count statistics. Background UR and ASL were recorded on both Both sides of the reflection. The ratio of the crest counting time to the background counting time?: 1. The wave diameter of the incident ray was 0.0mm, and the distance between the recognition detector and the crystal was 40000 mm. The data naturalization was 0. A total of 111 reflections were collected. Intensities ¥ Representative reflections measured after every 1,001 reflections that remained stationary during data collection showing crystal stability and electronic stability (no decay correction was used) 0 The linear absorption coefficient of 00160 is YY) cm' . An experimental absorption correction based on azimuthal scans for multiple reflections was used, which resulted in permeation coefficients (Ne) ranging from (iL), - A correction to the data to compensate for the Lorentz effect and the polarization effect. 9/11 | a

4.0 AA Cell Determination (Yo) Range) Omega Scan Peak Width at Mid-Height LY Lattice Variables: M - A(T) MoT A (Y) 1.07 = b 1 'A (Y) h TA (G) 0773 eae ol ees damping Zr Ce (coefficients L per chip: b mkk every 5 (EV,A 9711 )

z/min (in omega) 0 Scan rate (sweeps) £) z Lorenz corrections - Polarization Absorption (0.. 0 = AT (Emission coefficients: LHSU) A [aussie 9/1 i

positional variables and B (equivalent) of the compound z_05yy0

_ P Tv — #0) 07) 03)

HY) i) (0) It should be obvious to person 53) Ordinary skill that other embodiments have not been specifically disclosed J a However within the scope and spirit of the present invention and therefore the description in this application should not be taken as limiting the invention in any way Except as provided for in the following safeguards.

Claims (1)

6p 0 elements baad 1 1 - A process for preparing a crystalline amifostine composition OY includes the following steps: a Preparation of a formulation including amifostine and alcohol elas ¢ in which Ratios of amifostine, alcohol °C and water such that a particle-free solution was obtained at 1 °C ranged from about room temperature to about 10 °C; Which also provides a crystalline precipitate of amifostine upon cooling below the temperature ta ia A 5 8 b- Cooling the aforementioned formulation to a temperature below zero degree Ye for a period of time sufficient to cause the precipitation of amifostine the crystallizer; and D, 11, c- Vacuum drying of the resulting mixture to leave a solid crystalline amifostine OY, which has an enhanced degree of stability. 10? - The process according to claim sete (1), which additionally includes the introduction of a sterile inert gas over the aforementioned preparation after completing the vacuum drying of step (c). 1 * - The process according to claim (?) in which the selection aforementioned inert gas ? .From the group consisting of argon 0, nitrogen and helium o — $ _ 1 ¢ = the process according to claim (1) for which the temperature of step (b) Y is about the eutectic eutectic of said formulation 2 1 > - the process according to claim (;) which furthermore includes; after step “- (b); raising the temperature of the resultant mixture to a hardening temperature which is about (Ja) YF about a Yo highest said eutectic temperature; followed by ¢ by cooling the temperature of the mixture degenerated from the ian (lanl heat) of said eutectic back to said eutectic temperature or less before 1 performing step (z) 1 > = Claimed process (£) for which the stated eutectic temperature ¥ is in the range of about ya m to about — Ae 1 m 7 - Claimed process (0) For which said solidification temperature Y lies in the range of oy about a Vem to — a Ye. Said eutectic temperature YF lies in the range of about zero to about A = M. A) = the process according to claim (1) in which said formulation ¥ includes about oor gram to about 500 mg amifostine per milliliter of formulation formulation and about 71 to 775 (by volume) 3 alcohol ¢ and about 744 ax to (by volume) water. formulation Le which includes (1) the process according to the claim - > 1 mg to about 0*7 mg amifostine 175 mentioned about Y (on 01 and about © to formulation per milliliter of composition amifostine v; and approximately 7860 to 799 (volume basis) water. = 1 01 per milliliter of amifostine formulation (mg amifostine 001 mentioned approx. 7 150 base vol) alcohol 8160001 and approx. 01 se) and approx. formulation; | (Based on volume) Water. 11 1 The process according to claim (1) in which the said temperature Y of step (b) lies in a range of about a o— to about . 11-1- The process according to claim (1); in which the said temperature Y of step (b) is about —” XY m 1” 1 - process according to claim (1) which additionally includes a sterilization step. VE) - process according to claim (VF) in which said sterilization step Y includes sterile filtration of the formulation Step 0 mentioned before cooling. 9/1 i gv - - : 11 1 - The process of claim (0) or (5) or (0) or (V8) in which the said crystalline amifostine 7 is an amifostine hydrate: -hydrate of amifostine y 11 1 = the process of claim (0) or (8) or (0) or (V6) in which the said “crystalline amifostine” is an amifostine trihydrate trihydrate Y.: 17 1- The process of claim (0) or (£8) or (0) or (V8) in which the said “crystalline amifostine” contains from about 1 molecule to about ?so” 7 crystal water. VA 1 = process of claim (1) or (2) or (©) or (V2) in which Y includes the said composition amifostine formulated 11 1 - The process according to claim (VA) in which the said excipient is selected from the group consisting of sodium chloride, glycine 1, dextrose and sucrose sucrose and mannitol .mannitol 71 1 - Process according to claim (VA) in which formant y excipient is mannitol 911 0" M4 - 1 1 - A process for preparing a crystalline amifostine composition that includes the following steps: 1 a. prepare a formulation comprising about © 0 mg to about Yoo £ mg amifostine per milliliter of said amifostine 2; and about 7/ to about 770 (by volume) 1 ¢ ethanol and about 7/ to 737 (by volume) water and optionally. l about © milligram to about 01 mg excipient Flas a pharmaceutically acceptable A per milliliter of deformed formulation so that a solution free of particles is obtained at temperatures ranging from about 10 room temperature to about 10 C.; But the crystallized precipitate 11 of amifostine upon cooling below zero degrees; b. Cooling of said LS all formulation to a temperature which is in the range of 17 from about -© Ja about fom m for a period of time sufficient to cause 0 precipitation of “lial amifostine” and yo c._drying in Vacuum the resulting mixture to leave amifostine 0 as a solid crystalline preparation with enhanced stability. YY - Process under claim (1) or (4) or (©) or (YY) in which “the step(s) taken after step (a) and before step (c) are performed over a period of A period of ¥ of about vo-hour to about VY-hour. YY) - operation of claim (1), (8), (0), or (VY) in which “ - the step(s) taken after step 0 (and before step c) over the EV period Ja lajie TY an hour to about; 7 hours. YE) = the process under claim (0) or (8) or (0) or (71) in which 7" step (c) is performed over a period of about 1 hour to about VY hours. Y 1: = the process under claim (1) or (4) or (0) or (1) in which step Y (©) is performed over a period of about 0 hours to about 0 hours. Approximately 1.0 milligauris. Yo.millitor.YA 1 = the process according to claim (1) where the alcohol is ¥ an alkyl alcohol and YE) = the process lk of claim (1) ); Cua the alcohol is chosen from the Y group consisting of methanol « ethanol » and propanol l propanol » and isopropanol » and —n-butanol n -butanol sc - $560-5018001; and tert-butanol « and —n-pentanol n-pentanol ° and —Y-pentanol .2-pentanol 1/11 0.0 - 0 1 - A process for preparing a crystalline amifostine composition comprising Waltz-Y includes the following steps: i) v Preparation of a formulation 5 — containing about 100 mg ¢ amifostine per milliliter of formula (35524) and about 110 milligrams formulated excipient pharmaceutically acceptable per milliliter of formula | + mentioned and about 717.9 (by volume) a solution of VY ethanol distilled in water so that a solution free of precipitate is obtained at about A room temperature; and 8 (b) cooling said formulation from room temperature to about Yoo Ye m; at about 0 minutes; and 11 (c) maintain the said formulation at about Tom C for about OY 750 minutes to form crystalline amifostine nuclei ¢ and OY (d) As said formulation to about zero; in about 0 yo min; and 10 (e) maintaining the said formula in about zero; for about OT 100 minutes to solidify the nuclei and precipitate crystalline amifostine; and VY (f) cooling of said formulation from about zero to about Vom 2 YA at about 15 minutes; and 0 (g) the cooling of the said formula from about = 10 C to about co Yom Ye in about 1701 minutes; and 71 (h) maintaining said formation at about Wm for about 7 181 minutes; and YT (i) discharging air around said formation to a pressure less than about Ev) 0 YE: 01 * 01 μm; and z Ye (j) heating of said formulation from about Tom to about em m3 over about 84 hours; and vv k) maintaining the aforementioned formulation at about Yom C for a period of about 11 4 hours to about YE an additional hour to leave a crystalline amifostine 4 formula with enhanced stability. - 71 1 = crystalline amifostine prepared according to claim process (1(50)7) or (59)a () (a) () or (8) or (4)a (01) That (71) see (301). which is Loss constant; sterile; suitable for reconstitution with an acceptable carrier; - pharmacologically in a particle-free injectable lie product for non-intestinal administration to a human patient. TY = amifostine crystalline and which is prepared in accordance with claim (V7) “- which is thermally stable; and sterile; It is suitable for reconstitution with a pharmaceutically acceptable carrier T in a particle-free injectable ie product for non-enteric E administration to a human patient. VF = crystalline amifostine which is prepared according to the VA process and which is thermally stable; and sterile; It is suitable for reconstitution with a pharmaceutical grade Wie carrier in a particle-free injectable drug product for non-intestinal administration to a human patient.