US007420069B2 2) United States Patent 10) Patent No.: US 7,420,069 B2 Christensen et al. (45) Date of Patent: Sep. 2, 2008 (34) CRYSTALLINE COMPOSITION 2O0NODI2BS AL 1120 Tanck CONTAINING ESCITALOPRAM (75) tovenors:TroesVolguard Christensen, Hote FOREIGN PATENT DOCUMENTS (DK); Lene Andresen, Radovre DK); C* ner Shashank Mahashabde, Kendall Pik, C* ec LS NJ(US) Sebastian PeAssenza Fort sys Salongs, NY (US) cA poll 42000 : i oviss ——2ib86 (3) Asie: tami 8. Cpsus aby FF arse eae > oxerii6 289 *) Notice: Subject o any disclaimer. the termot this PP esis oe (7 me tegen mse Sh USC. 1540) by 437 days P ones 997 ip vet (21) Appl. Now 11/083,641 GB nist (21) Appl GB 2387762 7/2001 (22) Filed: Reb, 72005 wo Ja1s11 S188 WO wos9es6o L100 ) Prior Publication Data WO WOoO1106 wo Woot2 US 20050147674 AL Iu. 7, 2008 Ro woot Related US. Applicaton Data OTHER PUBLICATIONS (63) Continuation of application No. 10403,453, fled on ‘Mar. 31, 2003, now Pat. No. 6.916.941, which is a continuation of application No. PCT/DKO200513, filed on Jul 25,2002 G0) Foreign Application Priority Data JuL 31,2001 (DK) 2001 01168 (51) Inc. Co7D 3078 (2006.01) AGI 3134 (2006.01) (2) US. 549/467; 514/469 (58) Field of Classification Search... ‘S494467; 314/469 ‘See application ile for complete search history. 56) References Cited US. PATENT DOCUMENTS 3407675 A 911969 Paersen etal 4136,193 A 11979. Boges etal 4650884 A I9RT ogeso T2172 A 98S Baneset a 4943590 A 71990 Boogesoeet 5296507 A 1004 Tanaka eal 5683720 A 11/1997 Myers al S80.334 A L199 Raiden ea 586.098 A 21999 Mista S980941 A 11/1999 Raiden a 6916941 B2* 12008 Chrigemtenet un. S491467 2001/0049450 AL 122001 themoto etal ‘Webpage from Lundhec hse hindeck om) company’s tivities Sep. 26,2003 ‘Webpage fiom Lundback website (we tundbeck com): Product, infomation on Ciprat Sep. 26, 2005, Remington's Pharmaceutical Sciences, 18th Fon, Chapter 89, (ral Solid Dosage Forms, p, 1633-1688, 199, ‘Bhog B. Sheth etal, Compressed Tablets, Caper’ Parmacet tial Dosage Fooms: Tablets, vl 1, H.Licberman and. Lach ‘fs, Marel Dekker, Inc, New York an Basel, 1779. pp 109-185, (Chafers 2104 in Phaoacetcal Dosage Fos: Tablets, v1 icherman and. Lachman, ods, Marel Der Inc Now Yuk and ‘Basel 1989, pp. 75246 (Chapes 2 Tabet and Formulation Design, (Chapor3: Compressed Tables by Wet Granulation; Chapter: Com pressed Tables by Dice Compression} ‘KethMarcal,Compressonand Consolidation of Powered Sots, (Chaper 4, The Tory and Practise of Indus Pharmacy, Liber ‘man, Lachman, and Kaige. 3 ation, 1986, pp 669, (Continued) Primary Esaminer—D. Margaret Seaman Assistant Examiner—Nizal § Chandrakumar (74) tonne: Agent, or Frm—Darby & Darby PC « ABSTRACT Crystalline particles of escitalopram oxalate with a partile sizeof at less 40 ums disclosed. Method forthe manufacture of said ery saline particles and pharmaceutical compositions ‘comprising suid erystalline particles are also disclosed, 35 Claims, No DrawingsUS 7,420,069 B2 Page 2 (OTHER PUBLICATIONS. Hoener et, Chapter 4, Factors Influencing Drag Absorption and Drug Avil: Modern Pharsceties, rein, Banker and Rhodes, es, Marcel Dekker, Now York and Basel, 1995, pp 121- 1st ‘Edvard M. Rudi el, Chapter 10, Tablet Dosage Forms, Modern Pharmacctics, edition, Barker and thoes. els, Mares deer, ‘Now York and Basel 1995, pp, 333394. Josh B, Shwartz et a, Chapter 18, Optinazaton Techniques in Phamacctcal Formation and Procesing, Modern Pama, 3d Edion, Banker and Rhodes els, Mazel Dek J, New York and Basel, 1995, p. 727782. ‘Gansta, Chaper I, Tablets, The Theor and PraieofIndus- ‘al Pharmacy, eberman, Lachman and Kania eds 2nd Eton, 1976pp. 321-388 Keith Marshall, Chapter 10, Solid Oral Disage Fors, Modern Phannacatcs, Ist Elon, Banker and Rhodes, eds, Marcel Deke for, NewYork and Basel, 1979p, 350-47 ‘Vogels Texbook of Prastial Oganie Chemistry Fourth Eton, pp, 100.263, 178 _i-FitzGstimer, Profesor Phmazeutshe Technologie an der Universitat Bonn, 1973, Einuhrung in De Verhrenstechnik Der Aranitoriing, pp 201-203 and English asain), (O'Connor, RE etal, Chapter 9 Ponders, Remington: Te Seine and Prats of Phanaey, 1th Fa A. Genpar, editor, Mack Pb lishing Co, Eason, 1995, pp. 1598-1613, Banker, G'S, line formas the oxalate the hydobromide andthe ydrochlo- ride Slt, respectively. Furthermore, the citalopram base was oblainedasanoil (BP. 175°C./0.03 mmllg)-Thepublication also outlines the manufacture of tablets cootaning salts of citalopram. Citalopram is marketed as the hydrobromide and the hydrochloride, respectively. “Esitlopram, the pharmaceutical activity thereofand crys talline escitalopram oxalate are disclosed in US, Pat. No 4,943,590. Methods for preparation of pharmaceutical prepa ‘ations of escitalopram ar outlined. italopramis marketed ina numberof counces sa able. prepared by compression of granulated citalopram hydrobro- ‘ido, lactose and other excipients. I is well rognised that preperation of tablets with @ reproducible composition requires that all the dy ingredients have good flow proper Incases, where the ative ingreieat has good fw properties, ‘tablets canbe prepared by diret compression of the ingrei- ents. However, in many eases the particle size of the active substance is stall, the active substance is cohesive or has poor low properties. Farther, active substances witha smal particle size mixed with excipients having a lager particle size will typically segregate or de-mix during the abeting process » « 2 ‘The problem of small parle size and poor flowability is conveationally solved by enlarging the parce size of the active substance, usualy by gramain of the ative ingre- dient either alone on combination witha fillerandor other conventional tablet ingredien One such granulation mth sth “wet” granulation poe cess. Using this method, the de slid (active ingreicnts, fll, binder ee) are blended and moistened with water or another weling agent (ean aleobol) and agglomerates or aranules are bit up ofthe moistened sais. Wet massing is ceontnuod uni a desired homogenous particle size as ben achived wheretpon the pranlsted pacts died An allematve to the “wet” granulation method isthe “melt” granulation, which is also known as the “them plastic” granlation process, whete a low meking solid is sed asthe granulation agent. Inia, the dry sli are blended and hextd unl the Biner mek. As the binder is ligafi and spreads over the surace of the piles. the patcles will adhere to each otber and form granules. The bindersoffies upon cooting arming dry granlarproct, ‘Wet granulation a5 well as mel granulation are energy intensive uit operations requiring complicated and expen- sive equipments well a technical sil ihe active ingens, however. as suitable ow proper ‘cs, then the granulation ste an be aided an ables may be prepared by diet compression which isa cheaper pro duction meth. The process used forthe preparation of citalopram hydo- ‘ome rests ina prodoet witha very smal panicle ize around 220 yn ats many oer prtculate products with ‘small parle size, his very pooe New properties. This, ia certo achieve appropriate dosing ofthe citalopram hyo- tomide during tableting, t was considered nocessary’ 10 snake a granulate of citalopram bydrobromide with larger Patil ize and improved ow proper. ‘The citalopram abet thatismarkete stable made from griuliteditlopran hydrobromide wit various excipients ‘Weave found that xitalopram as significantly erent solubility and sal formation properics fom the citalopram rocemate For example theonly pharmaceutically crystalline saltknown so faristhe oxalate, wheres the etalopram rce- ate fomserstalinhydrobromie andhydehloie sls aswell ‘The escitalopram oxalate product prepared by erystliza tin from aetone as ound in US. Pat No. 498,590 hs, athe cglopram hytrobromide prodoct deseribed abo, a ‘ery small atl ize around 220 pn esting in siialy oor fo properties, Ta view of the fit that dist compressions much simpler and cheaper than te processes involving granulation there is a desi for larger crystals of escitalopram or phamacentical accelable addition salts hero Extensive laboratory adil scale esearch resutedin anew and invenive erystallization process producing lrger stalin particles of escitalopram oxalate, particles ofa Size cosparable to the size of the fille. Said parties are wf for the manufacture of dire compressed tablets “Accurate dosing in capsules may also be wih such lage particles OBJECTS OF THE INVENTION Its the object ofthe present invention to provide large crystalline particles of exctalopram oxalate suitable forse in iret compression,US 7,420,069 B2 3 A second object ofthe invention isto providea method for rmanofecture of lange crystalline particles of escitalopram. oxalate ‘A thind objet of the invention is to provide a novel phar- ‘maceutical unit dosage fom containing large crystalline par- ticles of escitalopram oxalate, wherein said unt dasage form ‘may be a tablet, which preferably may be prepared by diret compression, ora capsule. SUMMARY OF THE INVENTION w The invention then, inter alia, comprises the following ‘lone or ia combination Cystallinepantclesof escitalopram oxalate witha median particle sizeof at least 40 yum and suitable for use in a solid. 1S ‘unit dosage form. ‘A method for the manufacture of crystallin particles of csctalopram oxalate having a median particle sizeof at east. 40m and suitable for use ina solid unit dosage form wherein said method comprises that a solution of escitalopram oxalate ‘na suitable solvent sytem at is temperature gradually cooled down to a second temperature maintaining @ con- ‘eoled cooling profileand seeding the ey salizationbatch by addition of crystals of escitalopram oxalate atleast once during the cooling and follawed by a holding time at said 2 second temperature whereupon sad erytals are isolated by conventional solid/liquid separation techniques. ‘A solid uit dosage form comprising escitalopram pre- pered by dict compression of @ mixture of escitalopram, ‘ase ora pharmaceutically accepable salt thereof and phar- :maceatically acceptable excipients, or by fling of sid mix ture in a hard gelatin capsule, “The direct compression of escitalopram, a filer and oer pharmaceutically acceptable excipients into tablets bas the ‘ueat advantage, that the granulation and a drying step is avoided, Further as the granulation step is avoided, ti n0 longer necessary to ald binding agent. Asused herein, “escitalopram oxalate” means any addition salt consisting of escitalopram, oxalic acid and optionally ‘water. Example of such sltsarethe hydrogen oxalate salt of escitalopram, ie. the salt consisting of one molecule of esci- talopeam per molecule of oxalic aid, a8 wel s the oxalate salt of escitalopram, i the salt consisting of two molecules of escitalopram per molecule of oxalic acid, As used herein, “erstalline particles” means any combi sation of single ental, aggregates and agglomerates As used herein, “rect compression” means that the solid ‘unit dosage form is prepared by compression of simple rnixtur ofthe ative ingredient and excipients, without the active ingredient having boon subjected to an intermediate sranulation process inorder to embed it ina larger particle ‘and impaove is uit properties Asnsed herein, “bindee” means an agent, which s used in \wet or melt granulation processes and acts asa binder in the sranulated product. 'As used herein, “particle size distribution” means the ccumlative volume size distribution of equivalent spherical iameters as determined by lose diffraction at 1 bar disper- sive presure ina Sympatee Helos equipment “Median par ticle size”, correspondingly, means the median of said par- tice size distbution. As used hero, “refluxing temperature” means the tem- perature at which the solvent or solvent system relluxes or boils at stmospheric pressure. 6 As used hee, “cooling profil” means the femperctur of the crystallization batch a a fageton of ie. x“ 4 As used herein, “cooling rate” means the decrease in em perature pe ime unit “Thus ia one embodiment ofthe present iavention the ery talline particles of escitalopram oxalate have a median pat ticle size oft least 40 um, preferably in the range of 50-200 am. low, segregation and demixing properties and, hence, the suitability ofthe escitalopram oxalate crystals fr direct com pression depend, besides the median particle siz, on the particle side distribution. TInanothee embodiment ofthe present invention erystalline particles of escitalopram oxalate having @ median particle Size oft least 40 um, preferably inthe range of 50-200 um, and suitable foruseina sold unit dosage formare crystallised froma solution of escitalopram oxalate in a suitable solvent system, Said solvent system may comprise one or more aleo- hols and optionally water, preferably the solvent system is cthanol, Escitalopram oxalate is preferably dissolved inthe solvent system at temperature in the range bowen 50°C. and the reluxing temperature of the solvent system, prefer- ably between 60° C. and the refoxing temperature and more prefered between 70° Cand the refluxing temperature, sit- ably the escitalopram oxalate is dissolved atthe refluxing temperature. The amounts of pharmaceutically accepable salt of escitalopram and solvent used are preferably comre- sponding to a solutsolvent weight ratio in the range of (0.05:1 10 0.6:1, more prefered (11:1 10 05:1 and most pre- ferred 0.2:1 to Ot: The solution of eseitalopram oxalate is sradually cooled downto the temperature, at which the ery tals willbe isolated from the mother liquor, inthe range of 0.20" C., preferably 0-15° Cand more prefered 7-15° C ‘maintaining a controled cooling profile so thatthe cooling ‘tein an inital cooling period doos not exceed 0.6° Cnn, and preferably the cooling rate is kept within the ange of (02-0.4° Cin, and sud initial cooling period extends until the temperature ofthe crystallization batch is below 60° C., preferably below S0° C. and more prefered below 40° C., suitably the cooling rate may’ be kept in this range forthe centre cooling. The crystallization batchis seeded addition of crystals of exitlopram oxalate atleast once during the cooling time inorder to avoid excessive supersaturation with respect to escitalopram oxalate and resulting spontaneous crystallization into small crystalline particles. The seeding is preferably repeated in order to ensure constant presence of crystalline esitlopram oxalate during the cooling, suitably ‘the crystallization batch s seeded semicontinuosly until erys- ‘alization has started. The enystallization batch is kept at sid. second temperature for holding time for erystal growth for atleast I hour, prelerably inthe range of 4 to 24 hours and ‘more prefered 6 10 12 hours. Affer suid holding time, the crystalline particle of escitalopram are isolated from the ‘mother liquor using conventional separation techniques, filtration, none embodiment of the invention, the present invention relates toa tablet prepared from a mixture of large erystaline particles of escitalopram oxalate with a median particle size of atleast 40 um, preferably in the range of $0-200 jun and pharmaceutically acceptable excipients. Preferably the able is prepared by direct compression, In another embodiment, the present invention relates toa capsule prepared by filing @ mixture of lage crystalline panicles of escitalopram oxalate with a median particle size of atleast 40 um, preferably in the range of 50-200 yun and pharmaceutically aceptable excipients in shard gelatin cap- sale, Preferably, the solid unit dosage forms according to the invention do not contin a binder.US 7,420,069 B2 5 ‘Thesold unit dosage form according tothe invention may contain -60% ws active ingredient caleulated as escitalo- pram base, preferably 440% wis etive ingredint ealeu- Tated as escitalopram base, and more prefered 6-10% wie active ingredient calculated as escitalopram base. Suitably, s the solid nit dosage form ofthe invention contuins 8% wis ‘active ingredient calculate as escitalopram base. ‘The solid unit dosage form according tothe invention may contain a filler selected trom lactose, or other sugars e 8 sorbiol, mannitol, dextrose and suerose clei phosphates, (cibasie tribasic, hydrous and anhydrous), starch, modified starches, miroerysalin cellulose, caleium sulphate andlor calcium carbonate. na prefered embodiment, the slid unit dosage form of the invention does not contain lactose. ‘Suitably the filer is a microcrystalline cellulose such as ProSolv SMCC50 manufactured by Penvest Pharmacen cals or Avicel PH 200 manufactured by FMC Corporation, esides the active ingredient and filler, the solid pharma «ceutical unit dosage fos may inelude various other conven ‘ional excipients such as disinteyrants and optionally minor amounts of lubricants, colorants and sweeteners Lubricants used according to the invention may suitably be fone of more selected from the group comprising metallic stearates (magnesium, caleium, sodium), stearic acid, wax, hydrogenated vegetable oil, tale and colloidal silica. 2 Preferably the lubricant s one or more selected fom the roup comprising tle, magnesium stearate or calcium steat- fate, Suitably the lubricant isa combination of tale ands nesium stearate, The weight percent of magnesium stearate in. the solid unit dosage form is preferably in the range of 0.4% 102% aw more prefers in the range of 0.79% 0 L.%, Disintegrants include sodium starch lycolate,croscarmel- lose, crospovidone, low substitued hydroxypropyleelulose, ‘modified comstarch, pregeltiined starch and natural starch, Suitably the disntegrant is crossearmellose such Ac-Di-Sol ‘manufictnred by FMC Optionally the solid, pharmaceutical unit dosage form of the invention may be coated. Suitably the coating is a film coating based on conventional coating mixtures such as (Opaciy OY-S-28849, white manufactured by Colorn. The solid, pharmaceutical unit dosage form of the inven- ‘tion may be prepared by conventional methods using tablet press with fore feed capability: ‘The filled, hard gelatin capsule of the invention may be prepared by coaveational methods usin a capsule filler suit- able for powder fling. In the following, the invention is ustrated by way of examples. However, the examples are merely intended to illustate the iaveation and should aot be coasived as init. ing. x“ EXAMPLE 1 A wot filler cake obtained by precipitation of ene esit- ‘lopram oxalate by mixing of ethanol slutons of esc pram and oxalic acid, respectively, and containing appro mately 35 k escitalopram oxalate was suspended in 322 1. ethanol. The material Was dissolved by heating o reflux, and 150 L ethanol was removed by distillation. Cooling was applied andthe mixture was cooked fom eetuxto 15°C. with, ‘cooling rate between 0.2 and 0.5° Cnn a the temperature interval 80 to 40° C, During cooling, the mixture was seeded ‘with escitalopram oxalate at 75, 65 and 60° C. (10 g each time). The crystallization mixture was kept at 15° C. for 10 hours before the crystalline escitalopram oxalate was is0- 6 lated. Purified escitalopram oxalate (27.7 kg, 58.2% of ‘thoory) was obined by flation ofthe crystallization mix 6 ture, washing with ethanol and drying ofthe filter cake. Par- ticle size distribution forthe resulting escitalopram oxalate is lise in table TABLE 1 arene darbion Sy Hee oresiaepan one Sauls Pay SCM Qstle Example ‘rset seMCHO oo ) a) ‘” S > EXAMPLE 2 ‘Tablet Prepared by Direct Compression of Large Crystalline Particles of Escitslopram Oxalate ‘Tie Mole Gave) rss scca) wR6g neem) AeDeSa oe G6 Maggs ease BOE mw) Fim oa OpayONS 2068 shin 528g 2SuWafeow wes) Crystalline particles of escitalopram oxalate from example 1 and tale wore sieved through 710 yn seen and blended at ‘gpm foe 1S mining 100 liter Bohle PYM 200 mixer PoSolv 'SMCC90 and Ac-Di-Sol were added a bleading continued for 15 min, Magnesium stearate was sieved through 710 jm screen and added and blending continued for 3 mia 25 kg ofthe resulting mixture was tabletted (125.000 wb- {etshour ona Korsch PH 280 tablet press fited with oblong, ‘embossed, scored 53x mm punches. Tablet core weight as sett 128 mg. The nominal yield ws 200.000 tables. The {tablet press was run unl the mixture level was just above the forced feeder, ie, the tableting was continued as long as possible in order identify possible segregation tendencies inthe last quantities of mixture. The tablets produced had satisfactory techaical properties. The invention claimed is 1.A tablet prepared from a mixture oferystalline panicles of escitalopram oxalate having @ median particle size of 40-200 um and phamnaceutically acceptable excipients. 2. Thotabletofelaim 1, where the median particle sizeof the erystalline particles is fom $0-200 ya. 3. The tablet of claim 1, wherein the pharmaceutically accepicble excipients comprising a disinteprant, lubricant, colorant, or sweetener. 4, tablet prepared by directed compression of mixture of eysaline particles of escitalopram oxalate having a ‘median particle size of 40-200 ym and pharmaceutically acceptable excipients 8. Thetabet ofelaim 4, wherein the median particle sizeo the crystalline particles is fom $0-200 jum. 6. The tablet of claim 4, wheteia the tablet is coated, 17.The tablet of claim 4, wherein the tablet does not contain binder.US 7,420,069 B2 1 8. The tablet of claim 4, wherein the tablet comprises 1 30% w/w active ingraientcalelatedasesctalopram base 9, The tablet of claim 4, wherein the wblet comprises 4.20% wiw active ingredient calculatadas escitalopram ase. 10. The tablet ofclaim 4, wherein he tbletis substantially s free of lotoxe L.A tablet prepared from crystalline particles of esitalo- ‘pram oxalate having a median particle size of 40-200 jun, 12-The abletofclaim 11, wherein the median particle size ofthe crystalline particles is fom $0-200 um. vo 13.A method for preparing an excitalopram oxalate tablet comprising the steps of: () preparing crystalline particles of escitalopram oxalate having a median particle size of 40-200 um; and () preparing a tablet from te erystaline particles. 14. The method of claim 13, wherein the median particle size ofthe crystalline partite is from 50-200 um. 18. The method of claim 13, wherein the erysalline par ticles of escitalopram oxalate are prepared by: (@) dissolving escitalopram oxalate in a solvent at a first temperature between about SO” C. and the refluxing ‘temperature of the solvent o forma solution of escitalo- pram oxalate (b) gradually cooling the solution of escitalopram oxalate ‘oa secondl temperature between about °C. ane 20°C. 2 ‘while maintaining 2 controlled cooling rate; (c)adding crystals of escitalopram oxalate during the cool. ing of step (6) (4) holding the solution atthe socond temperature: and (¢) isolating crystalline particles of escitalopram oxalate rom the soliton, 16.Themethod ofclaim 18, wherein thesolventcontain at least one alcohol and optionally water 17-Themethod of claim 16, wherein the solvent comprises ethanol 18, The method of claim 18, wherein the solutesolvent ‘weight rato is between about 0.05:1 and 06:1 19. The method of claim 15, wherein the soltesolvent ‘weight rato is between about 0.1:1 and 05:1 20, The method of claim 15, wherein the solutsolveat ‘weight ratio is between about 0.2: and 04:1 8 8 21. The method of claim 18, wherein the first temperature is between about 60°C. and the refluxing temperature ofthe solvent system, 22. The method of claim 18, wherein the first temperature is between about 70°C. and the refluxing temperature of the solvent system, 23. The method of claim 1S, wherein the second tempera ture is berween about 0° C, an 15°C 24, The method of claim 1S, wherein te seoond tempera ture is erween about 7 C. and 15°C. 26, Themethod of claim 15, wherein the controlled cooling rate comprises an initial cooling period during which the cooling rate doesnot exceed 0.6" C. per minute 26. The method of claim 25, wherein the inital cooling petiod comprises the time between the slat af the cooling period aad the tie at which the temperate is below 60°C 27. The method of claim 25, wherein th inital cooling period comprises the time between the stat af the cooling period and the time at which the temperature is below 50°C 28. The method of claim 25, wherein the inital cooling period comprises the time hetwoen the stat af the cooling Period and be tine a vbich te lemperaeis below 40°C. 29. The method of claim 28, wherein the cooling rate is from 0.2 1004" C. per minute, 30. The method ofelaim 15, which comprises adding erys- tals of escitalopram oxalate at least to times during the cooling af step (). ‘31. The method of claim 18, which comprises holding the solution atthe predetermined temperature for at last one how: 132. The method of claim 18, which comprises holding the solution atthe predetenmined temperature for 4 to 24 hours, 3, The method of claim 18, which comprises holding the solution atthe predetermined temperature for 6 to 12 hours 34. The method of claim 18, wherein step (2) comprises isolating the crystalline particles of escitalopram oxalate by soldligud separation techies. 38. Themethod of elaim 18, wherein the soidiguidsepa- ration techniques comprise fileation