‘Arch Pharm Res Vol 27, No 3, 957-960, 2004 Crystal Forms of Ketorolac ‘Young-Taek Sohn and Hyun Ok Seo ‘Archives of parmacal Research Taeranepocone CColege of Pharmacy, Duksung Women's Univesity, Seoul 122-714, Korea INTRODUCTION PPharmaceutcal sls can extn trent cyst forme, ‘ch as erystatine, amorphous. or glass, and alo in ‘solvated oF hydrated states (Gorka, 100; Halobion ot ‘at, 1969; Haleblan, 1975: Kuhnee-Brandsaetr, 1973: Lachman oa, 1986; Stn, 1955). gonerl pobmortm defines 28 the aby ofa substance lo exist as to oF hydrate compounds is important since ther aqueous solblties can be sical les than their anyeous {os Conversion ofan ennycrous compound to a myeate \winin the dosage form may reduce the dssouion rate _and extent of ug absorption (Sher of at, 1963; Soh, 41994: Sohn ot af, 1993: Sohn ot al, 1996). However, eystaline polymorphism for ketorolac has not been 8y8- tematicaly studied inthe erature. Therefor, the aim ofINTRODUCTION Pharmaceutical sols can exis in diferent crystal forms, such a eystaine, amorphous, glass, and also in Solvated or hydrated states (Borka, 1991; Halobian ot at, 1968; Halebian, 1975; Kuhner-Brandstacter, 1973; Lacan ot a, 1986; Sob, 1995). goneral pobmohsm ‘eines a5 the abitly of @ substance fo exist a8 two OF ‘more cystaline phases that have ferent arrangements andlor conformations of the molecues in the crystal latice. Plymerphs share the same chemical composiion ‘but have diferent crystal structures. Because of their ‘timately,bioavalabity (Sohn, 1996; Sohn e al, 2002) A stoichiometric adduct, commonly refered to 38. solvate, is a molecular complex that has incorporate the {ystalizing solvent molecules ino spectc sites wihin the ‘crystal latice. When the incorporated solvent i wat, the ‘complex is called hydrate. Identification of possble hydrate compounds is important since their aqueous. solutes can be significantly less than thei anhyerous. forms. Conversion of an anhycrous compound to 3 hygrate wahin the dosage form may reduce the dissolution rate {and extent of chug absorption (Shefter otal, 1963; Sohn, 1994; Sohn ot al, 1993; Sohn of al, 1996). However, crystaline polymorphism for ketorolac has not boon sys ‘ematicaly studied in the Merature. Therefor, the aim of this study was to investigate the existence of diferent crystal forms of ketorolac, nonsoridal ant-ntammatory agent. MATERIALS AND METHODS Materials Ketorolac was donated ffom Pacifle Co. Lid, Seou, Korea. Other chemicals and solvents were of anatyical regent or special grade. Proparation of crystal forms of ketorolac Form 1 is the ketorolac standard and donated one, wich is identical to sold phase of recrystalizaton fom methanol. Form ll was obtained by dissolving in 1.4- ddoxane (150 mgimL at 25°C. The undissolved drug was fered off and the resultant soliton was then cooled at S'C. The obtained crystals were separated by fixing Under reduced pressure and died over silca gol ia Sesiccator a 25°. Form Il was prepared by dissolving in 1 4-dhoxane (150mgimL) at 25°C. The undissolved drug was fitered off ‘and the resuitant soluton was then cooled at 10°C. The ‘biained crystals wore separated by fitering under reduced pressure and cried as described for Form I, Form IV was obiained by dissolving in 14-doxane (150 maim) at 25°C. The undissolved drug was fitered off and the ‘esitant soluton was then cooled at -72C. The obtained cysts were separated by tering under reduced pressure and died as described for Form i Identification and characterization Xray powder dfacion (XRD) pattems were obtained with Rigaku DMA SHIA with Cu Ka raciation over the Interval 5-30728. The measurement conditions were 3s follows. Target, Cu; fiter, Ni vltage, 30 KV; curent, 20 ‘mA Difomtal scanning calorimetry (OSC) curves of tho sitferent crysialine forms were recorded on a Mottor Toledo, DSC 12E thermal analyzer. The thermal behaver ‘was studied by heating the crystal forms in a covered sample pan over the temperature range 35-200°C at a heating rate of 10°C, “Thermogravinetic analysis (TGA) was carried out on thormegravimotic system (Sako | SSC-5000) by recording mass 10ss of solvate over the temperature range 35- 300°C at a heating rate of 10°Cimin Dissolution test The dissoluion tests were according to the Korean Pharmacopela paddle method using a rotational speed (of 100 rpm at 3740.5°C. A fixed amount (10 mg, <100 mesh) of ketorolac crystal forms was placed into 1 L istiled water (pH 6.7) and at an appropriate intervals, {and an aiquot (1 mL) was withdrawn witha syringe and fitered trough a 0.48 jm membrane fiter(Milipore). In this study, 1 mL water at same temperature was replaced in the dissolution vessel. The concentration was spectrophotometicaly determined at 322 nm using ' Hewlet Packard HP 8452A diode-array spectropho- tometer Stability ‘Samples of Ketorolac crystal forms were stored in saturated salt solutions of two relative humdlios (75%, (0%) i desicaters at 2040.5°C for 60 day. RESULTS AND DISCUSSION Characterization of crystal forms of Ketorolac ‘The XRO pattems ofthe four crystal forms of ketorolac ‘are shown in Fig. 1. The XRD pattoms of tho four crystal forms are quite diferent. indicating that the four crystaline forms are indeed ferent. The XRD pattems were ‘consistent with the fact hat the four DSC patlems (Fg. 2) ‘wore also different. DSC profies obtained for Form I, Form i, and Form iit showed sharp endotherm poaks. corresponding tothe meting of ketorolac at 158°C, 157°C,| j iN J ] © 1 | ° all ai 1 | 4 i} Ni tissu ij Fig. 1 Xaystacton patos er kta tine forms, Pane Ae pat Form: Parl 8, be patiem fr Fr PaelC, be pation {or Fem it Pana. pate for Ferm.‘Crystal Forms of Ketorolac Fomt ‘and 153°C, respectively, The heats of fusion for Form 1, Form ll, and Form Il were 26.8 calg, 160.8 cali, and 238 calg, respectvely. Form IV had two endothermic peaks at 61°C and 191°C and ther heas of fusion were 9.3 callg and 6.7 cal. Fig. 3 showed TGA curves of the four cystal forms of ketorolac. According to the analysis, Form I land Il are ot apparently solvates. In contrast, however, Form IV showed the weight loss of a desolvation at S5-67C. Considering the fact that doxane was used as @ solvent in the preparation of the otal, an 1:1 molar ratio of ketorolac to dtoxane was calculated, and therefore Form [Vs tkely to be a pseudopolymorph. Dissolution behavior of crystal forms of ketorolac Fig. 4 shows dissolution profes of ketorolac crystal {forms in istiled water at 3720.5°C. The solubilty of Form |lwas the highest. The solubilty decreased in rank order: Form | > Form ll > Form Ill > Form IV. The solubility of Form IV was 64% of Form | ater 5,