Preliminary investigations into the behavior of urea: succinic acid co-crystals on scale-up by batch crystallizations

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(1)2008:067. MASTER'S THESIS. Preliminary investigations into the behavior of urea - succinic acid co-crystals on scale-up by batch crystallizations. Akinyemi Kamorudeen Amida. Luleå University of Technology Master Thesis, Continuation Courses Chemical and Biochemical Engineering Department of Chemical Engineering and Geosciences Division of Biochemical and Chemical Engineering 2008:067 - ISSN: 1653-0187 - ISRN: LTU-PB-EX--08/067--SE.

(2) PRELIMINARY INVESTIGATIONS INTO THE BEHAVIOR OF UREA SUCCINIC ACID CO-CRYSTALS ON SCALE-UP BY BATCH CRYSTALLIZATIONS.. Amida, Akinyemi Kamorudeen Experimental part of Masters Thesis Masters of Science in Chemical and Biochemical Process Engineering Lulea University of Technology Sweden. Division of Biochemical and Chemical Process Engineering Division June, 2008. 1.

(3) Abstract Keywords: solubility, urea, succinic acid, co-crystals, synthon Crystallization is an important method used for purification and in production of solid form of pharmaceutical products. Screening of urea and succinic acid in different organic solvents was conducted to identify the most suitable solvent for crystallization process. The screening process produced isopropanol as the most suitable solvent. Cooling crystallization was carried out using Julabo Easy Temp software for temperature control with 100Pt IKA temperature sensor inserted in the crystallizer for temperature monitoring. Solubility studies of urea-succinic acid co-crystals were conducted, using an HPLC method, to find a cooling profile so as to determine the effects of process parameters on the quality of products obtained. The solubility of urea-succinate cocrystals was found to be temperature dependent because at a fixed stirring rate, solubility decreases with decrease in temperature . DSC, PXRD, and Raman data confirmed the formation and stability of urea-succinate co-crystals on scale-up. The process parameters of stirring rate, cooling rate and temperature had no significant influence on urea-succinic acid co-crystals on scale-up.. 2.

(4) ACKNOWLEDGEMENTS My profound gratitude goes to Almighty God for his mercy, steadfast love, protection, and for making this long time desired ambition a reality. My profound appreciation also goes to my parents for their prayers, patience and understanding during the course of this program in Sweden. I acknowledge unquantifiable advice, suggestions and constructive criticisms of my Supervisor, Dr. Sitaram Velaga and Professor Kris Arvid Berglund in this work. A very considerable appreciation goes to David Hodge, Josefine Enma, Christian Andersson, Jonas Emerius, Magnus Sjoblom and to other members of staff in Chemical and Biochemical Process Engineering Division for their knowledgeable and valuable contributions to this work. My indebtedness goes to Professor Stefan Andersson and the Division of Pharmaceutics of Lulea University of Technology Sweden for the stipend and for giving me the opportunity to carry out the experimental part of this thesis in their Division. My appreciation also goes to academic and non academic of staff of the Department of Health Science for their co-operations and understanding. I acknowledge the contributions my late friend and brother Mr Olusola Joseph Adeniyi(R.I.P) whose useful advises and encouragements had been of immense benefit in accomplishing this task. I am greatly indebted to Denys Rublenko whose kind gesture, assistance, support and encouragement in accomplishing this task cannot be over emphasized. It is my desire to express my gratitude to my wife Liza, my daughter Ronke and Mavis Lagerkvist for their moral support and assistance. Contributions of Amjad Hahalawa and Benyong Lou is acknowledged. Amida, Akinyemi Kamorudeen June, 2008. 3.

(5) ABBREVIATIONS HPLC DSC PXRD RSD RPM UREA-SUCCINIC ACID API NMR TGA IR CSD mA kV InGaAs AUC SD SA µL. high performance liquid chromatography differential scanning chromatography powder x-ray diffraction relative standard deviation revolutions per minute urea succinic acid active pharmaceutical ingredient nuclear magnetic resonance thermogravimetric analysis infra red cambridge structural database milliampere kilovolt indium gallium arsenide area under curve standard deviation succinic acid microlitre. 4.

(6) CONTENTS 1 INTRODUCTION…………………………………………………… … 6 2 MATERIALS AND METHODS………………………………………...10 2.1.Crystallizations …………………………………………………..11 2.1.1 Screening or small scale crystallizations …………....................11 2.1.2 Scale-up (large scale)crystallizations…………………………..11 2.1.2.1 Solubility of co-crystals………………………………..11 3.SOLID STATE CHARACTERIZATION……………………….............12 3.1 Differential Scanning Calorimetry……………………………12 3.2.Powder X-ray Diffraction……………………………………..13 3.3 Raman Spectroscopy….……………………………………….13 4. RESULTS AND DISCUSSIONS……………………………………….14 4.1 Crystallizations…………………………………………………..14 4.1.1 Screening or small scale crystallizations ………………….14 4.1.2 Scale-up (large scale) crystallizations …………………….16 4.1.2.1 Solubility of co-crystals…………………………….19 4.1.2.2 Scale-up of co-crystals……………………………...22 5. CONCLUSIONS………………………………………………………….23 References…………………………………………………………………24. 5.

(7) 1.0 INTRODUCTION Crystallization is known to be one of the important methods used in production of solid form of pharmaceutical products. In addition crystallization can also be used in purification of solid compounds. Crystallization is based on the principles of solubility in which solutes are more soluble in hot solvents than in cold solvents. A typical crystallization process in a liquid phase is a binary system with the solvent and the compound to crystallize as the solute. 1 In any case, the crystallization process may not be as simple as expected especially on large scale production. This is due to some challenges it may pose in predicting the influence of processing parameters including stirring rate, cooling rate, vessel geometry configuration, temperature, type of impeller, seed crystals, supersaturation, additives and impurities5-8 on the process behavior, particle quality and particle size distribution.2 But additives are considered as secondary factor in crystallization while agitation rate and temperature are primary determinants. 3-4All these above mentioned parameters are considered as the factors affecting cooling crystallization on scale-up. During crystallizations, a supersaturation is created as the driving force for particle nucleation and crystal molecular growth. The supersaturation transforms aggregate into agglomerate while agitation is important in particle agglomeration, this is because turbulent fluid motion is responsible for particle collision and aggregation.5 Both thermodynamic and kinetic factors play important role in influencing the quality and particle size distribution of pharmaceutical products. It has been reported that a particular form of polymorph may be predominant on screening stage and turn out to be. 6.

(8) affected by kinetic factors on scale-up 6. In this regard, optimization of particulate processes is important because cooling rate and stirring rates have significant effects on crystal size, particle quality and particle size distribution most especially in pharmaceutical products. For example, the products that have needle shapes, high agitation rates can destroy the shape resulting in fine particles which can make down stream processes like filtration, more difficult. 7 Some pharmaceutical products have poor dissolution rate, solubility, chemical stability and moisture uptake 8. Poor solubility may affect their bioavailability and eventual therapeutic efficacy. The physicochemical properties of these products can be improved by obtaining co-crystals using crystallization. Co-crystallizations may be referred to as a complex of two or more covalent bonds called hydrogen bonding.9 Co-crystals have a synthon which is a structural unit within a molecule which is related to a possible synthetic operation that directs molecular assembly. Hydrogen bonding has been one of the most interactions because of its strength and directionality in building a large molecular networks. For example urea succinic acid synthon has hydrogen bond linkage.. H H O │ │ ║ H─O─C─ C ─ C─ C─O─H ║ │ │ O H H Succinic acid. H─N─H │ O=C │ H─N─H Urea. │. 7.

(9) Figure 1 The figure 1 above is urea-succinic acid synthon with a molecule of succinic acid and one molecule of urea. One molecule of succinic acid on the left hand side is linked to one molecule of urea on the right hand side by hydrogen bonding which are in dotted lines. The oxygen atom in urea molecule is bonded to hydrogen atom in succinic acid molecule (top dotted lines) while oxygen atom from succinic acid molecule is bonded to hydrogen atom from urea molecule( bottom dotted lines). Co-crystals and salts may sometimes be confused but there is a clear distinction between them. Salt formation is a three component system having an acid (A), a base ( B) and one or more solvents. A salt is formed by transfer of a proton (H+ ) from an acid (A) to a base( B). The majority of the drugs are basic B and therefore the main task is to select a suitable acid former. A-H + B→ (A-)(B+-H) A co-crystal is an A-B composite in which no proton transfer has occurred and this may be due to the fact that the pKas are generally less than for the salts and it is likely that the pKa values for the bases are not sufficiently high enough to allow proton transfer.9. 8.

(10) A-H + B→(A-H)(B). The formation of a salt or a co-crystal can be predicted when the pKa values are known as illustrated by the table below.. Acid. Compound Succinic Acid. pK1 4.2A. Co-crystal Benzamide forming bases 2 Pyridone 3-(4-pycolinyamino) cyclo hex-2enone aminopyrimidine (p-cyanophenyl)imidazolylmethane. Salt forming bases. * 0.7B 5.7B 3.9B 6.1B. Urea Phenazine 2- amino- 6 –ethyl- 4 (3H )pyrpyrimidone. 0.1B 1.6B 0.5B. piperazine Doxylamine. 9.8B 8.7B. L -Lysine. 9.5B. Imidazole. 6.9B. Ethylene-1,2- diammonium. 9.9B. Table 1: Co-crystal and salts of succinic acid with their corresponding pK1 values A indicates an acidic pKa. B indicates a basic pKa. *pK1 of this compound has not been reported in the literature. 10. The rule of three may serve as a guide to know when a salt or co-crystal is formed. It states that the salt formation generally requires a difference of at least three pKa units between the conjugate base and the conjugate acid. pKa(base) - pKa(acid) ≥ 3 where pKa 9.

(11) is the ability of an ionizable group to donate a proton(H+) in an aqueous medium and is often referred to as dissociation constant.10 When a salt is formed the differences in pKa values between the acid and the base are greater than 2.7 and so are in accordance with rule of three11 while pKa values are less than 3 in co-crystals. This scale-up study involves making a solubility study to find a cooling profile in order to know the effects of the process parameters, agitation rate, temperature, cooling rate additives and impurities on product quality. The motivation behind this work is to investigate the influence of process parameters on scale up of co-crystals .This is of paramount interest in pharmaceutical industries because of the tendency of some products forming polymorphs on scale-up as a result of the influence of process parameters, and this area has not been exhaustively explored.. 2.0 MATERIALS AND METHODS All chemicals (purity >99.9%) and Solvents (purity >99.8%) were obtained from Sigma Aldrich, Stockholm, Sweden and were used without further purification. MilliQ water was used.. 10.

(12) 2.1 CRYSTALLIZATIONS 2.1.1 SCREENING OR SMALL SCALE CRYSTALLIZATIONS At the screening stage, several organic solvents methanol, ethanol, 1-propanol and 2 – propanol(isopropanol) were used to dissolve urea and succinic acid at elevated temperature of 60°C. At small scale, 118.0mg succinic acid and 60mg urea (1:1) were dissolved in 10ml of isopropanol and heated to 60°C for dissolution, and left for 3 days at room temperature for crystallization to occur.. 2.1.2 SCALE-UP (LARGE SCALE) CRYSTALLIZATIONS For scale-up (17.7g) 0.15mole succinic acid was mixed with (9.0g) 0.15 mole urea (1:1) and mixed in 380ml of isopropanol. The mixture was heated to achieve dissolution and a few crystals were left at the bottom of the crystallizer at 70°C,equilibrated for 1.00 hour and then the mixture cooled down to 12°C. An agitator of 30cm length was used for agitation, agitated by IKA Eurostar digital stirrer at 100rpm. Repeat crystallizations at various cooling rates and agitator speeds were carried out in the same crystallizer with same recipe for other batches. Julabo Easy Temp software was used for temperature control, 500ml jacketed crystallizer fitted with a condenser, 4liter circulating water bath, 100 Pt IKA temperature sensor was inserted. Samples were collected at different temperatures using a long filter fitted with a 1.0ml syringe. 2.1.2.1 SOLUBILITY OF CO-CRYSTALS Urea and succinic acid were obtained as high purity solids from sigma chemicals. Primary standards of urea and succinic acid were prepared by serial dilution in a mobile. 11.

(13) phase at pH 2.5 (98% distilled water, 2%Acetonitrile HPLC grade,50mM KH2PO4) Succinic acid and urea were measured by HPLC(series 200Quatenary LC pump and UV-Visible detector Perkin –Elmer) equipped with a C-18 column(ultra aqueous, 5µm, 150mm x 4.6mm, Restek) using a 50mM KH2PO4 buffer with 2% acetonotrile(pH 2.5 adjusted by HCl) at a flow rate of 0.35ml min-1 as the mobile phase with a 20µL of sample injected manually for analysis with a U.V detection at 210nm. Peak areas from chromatogram were evaluated by comparison to standard curves prepared from solutions with known concentrations of succinic acid and urea. All data were colleted and processed using Perkin Elmer’s TotalChrom analytical software. Standard graph was obtained for urea and succinic acid by HPLC method and the solubility of the urea succinic acid co-crystal was determined by taking 1.0ml of urea succinic acid slurry and dissolve in 9.0ml of distilled water at 60°C,50°C,40°C,30°C,20°C 15°C and 12°C. The solubility data were obtained by HPLC method at 60°C,50°C,40°C,30°C,20°C ,15 °C and 12°C respectively.. 3.0 SOLID STATE CHARACTERIZATON 3.1 DIFFERENTIAL SCANNING CALORIMETRY(DSC) Thermal analyses of the samples were performed on a Thermal Advantage DSC Q1000 V9.8Build 296(TA instrument-waters, LLC) module which was calibrated for temperature and cell constants using indium and sapphire. Samples (1-2 mg) were crimped in non-hermetic aluminum pans(30µl) and scanned at a heating rate of 10 °C/min in the range 30-300°C under a continuously purged dry nitrogen gas, and quality detector,(flow rate 50ml/min). The instrument was equipped with a refrigerated cooling. 12.

(14) system. The data were collected in triplicate for each sample and were analyzed using TA Instruments Universal Analysis 2000 V4.3A software. 3.2 POWDER X-RAY DIFFRACTION (PXRD) PXRD patterns were collected on a Siemens DIFFRAC plus 5000 powder diffractometer with a Cu K radiation (1.540 56 Å). The tube voltage and amperage were set at 40 kV and 40 mA, respectively. The divergence slit and anti-scattering slit settings were variable for the illumination on the 20 mm sample size. Each sample was scanned between 5° and 50° in 2 with a step size of 0.02°.The instrument was calibrated using a silicon standard. The experimental PXRD patterns and simulated PXRD spectra from single-crystal structures were Rietveld refined using TOPAS R (version 2.1, 2003) and Powder cell (version 2.4, 2000) and were compared to confirm the composition of the materials . Small scale and large scale co-crystal samples were partially and ground put into a sample holder and inserted inside the PXRD. The solid phases of co-crystal were analysed by X-ray powder diffraction and the patterns compared to co-crystal simulated pattern and to the diffraction pattern of each pure phase. 3.3 RAMAN SPECTROSCOPY Raman spectroscopy probes the effects of the structure of a compound on a vibrational energies. The Raman spectra were recorded on a Perkin-Elmer near-IR FT-Raman 1700X spectrometer equipped with an indium gallium arsenide (InGaAs) detector. An excitation wavelength of 1064 nm of Nd: YAG laser radiation (power 400 mW) was used. A total of 50 scans were collected from 4000 to 400 cm-1 for each sample. Data were analysed using spectrum software. Resolution was 4 cm-1.. 13.

(15) 4.0 RESULTS AND DISCUSSIONS 4.1 CRYSTALLIZATIONS. In both small scale and large scale co-crystals obtained were needle shaped white colored crystals when viewed under optical microscope. The particle deposition or nucleation was observed between 65°C -68°C during cooling crystallizations.. 4.1.1 SCREENING OR SMALL SCALE CRYSTALLIZATONS The screening stage resulted in isopropanol as the most suitable solvent for the formation of urea and succinic acid co-crystals. Isopropanol is a solvent of choice because it dissolves urea and succinic acid better than other solvents tried. The DSC data below confirms the co-crystal of urea succinic acid. The melting point of succinic acid is 188.9ºC and urea is135.3 ºC while the melting point of the co-crystal is 149. 9ºC (Figure 3.). 14.

(16) 5. Heat Flow (W/g). 0. -5. ––––––– –––– ––––– · ––– – –. -10. Succinic Acid Raw material R1147.08°C Urea Raw Material R1 UreaSuc propanol R1 UreaSuc EtOH R1. -15 135.26°C. 149.90°C. -20. -25 20. Exo Up. 188.97°C. 40. 60. 80. 100 120 140 Temperature (°C). 160. 180. 200. Universal V4.3A TA Instruments. Figure 3: DSC pattern of urea, succinic acid, urea-succinic acid co-crystal formed from isopropanol, and urea succinic acid from ethanol at laboratory scale.. POWDER X-RAY DIFFRACTION(PXRD) The diffractograms of urea and succinic acid crystals are different from urea-succinic acid co-crystal. The sharp peaks of diffractograms confirmed high crystallinity of the co-crystals. The diffractograms were obtained for small scale urea-succinic co-crystals, urea raw material and the succinic acid raw material. The PXRD pattern for small scale urea-. 15.

(17) succinic acid, which was taken as a reference was conspicuously different from its individual components.( figure 4).. PXRD PATTERNS FOR LAB SCALE UREA-SUCCINIC ACID COCRYSTAL,UREA AND SUCCINIC ACID RAW MATERIALS. 10000 9000 8000 7000 6000 5000 4000 3000 2000 1000 0. Intensity. figure a figure b figure c. 0. 10. 30 2 Theta 40. 20. 50. 60. Figure:4 Comparison of PXRD patterns of urea-succinic acid; a: labscale co-crystal of urea succinic acid, b :urea-succinic acid at 12ºC,figure: c urea succinic acid at 60ºC,cooling rate at 10ºC/hour and agitation rate 150rpm. RAMAN SPECTROSCOPY Figure 10 showed Raman spectra of pure urea, pure succinic acid, small and large scale urea-succinic acid co-crystal . It is obvious that the effects of the structure of a urea-succinic co-crystals on vibrational energies remain the same on scale up. 4.1.2 SCALE-UP (LARGE SCALE) CRYSTALLIZATIONS The results obtained from DSC,PXRD and Raman spectroscopy on crystals formed at large scale were quite similar to the controlled reference laboratory(small)scale. The effect of temperature and cooling rates at a fixed stirring rates did not influence the stability of the urea-succinic acid co-crystal as can shown by figures 8, 9 and10.. 16.

(18) 5. Heat Flow (W/g). 0. -5. -10 ––––––– –––– ––––– · ––– – –. -15. -20 Exo Up. 0. UrSuc 40C Isoprop Expt8 UrSuc 30C Isoprop Expt8 UrSuc 70C Isoprop Expt8 UrSuc 12C Isoprop Expt8. 50. 100rpm 100rpm 100rpm 100rpm. 100. 150. Temperature (°C). 200. 250. Universal V4.3A TA Instruments. Figure 8.DSC for urea-succinic acid co-crystal obtained from isopropanol on large scale at different temperatures, agitation rate at100rpm and cooling rate of 5°C/hour.. 17.

(19) PXRD PATTERNS. 30000 25000. figure a. 20000 Intensity 15000. figure b figure c figure d. 10000 5000 0 0. 10. 20. 30 2 Theta40. 50. 60. Figure: 9 Comparison of PXRD patterns of urea-succinic acid co-crystals; a: laboratory scale urea-succinic acid co-crystal, b: urea-succinic co-crystal at 12 ºC, c: urea-succinic acid at 30 ºC, d: urea-succinic acid at 70ºC ,cooling rate at 5ºC/hour and agitation rate 100rpm.. large scale urea-suc acid. lab scale urea-suc acid INT. pure suc acid. pure urea 4000.0. 3000. 2000. 1500. 1000. cm-1. Figure 10: Raman spectra for pure urea, pure succinic acid, lab scale urea-succinic acid co-rystals and large scale urea-succinic acid co-crystals at 12ºC, cooling rate at 10ºC/hour and agitation rate at 100rpm. 18. 400.0.

(20) 4.1.2.1 SOLUBILITY OF CO-CRYSTALS The standard graph was plotted to in order to determine the solubility of urea-succinic acid co-crystals. The area under the curve obtained for urea in urea-succinic acid cocrystal was inserted into urea standard graph equation in order to obtain the concentration of urea at a particular temperature. For succinic acid as well, the area under the curve obtained for succinic acid was fixed into succinic acid standard graph equation in order to obtain the concentration of succinic acid at a particular temperature.. Succinic acid. Theoretical value 5 4 3 2 1 0.5. Actual value 5.0066 4.00528 3.00396 2.00264 1.00132 0.50066. Run1. Run 2. Run 3. AUC 13469306 10977000 7970595 5381893 2684163 1346187. AUC 13304235 10887037 7919078 5377251 2680531 1342913. AUC 13280249 10901212 8011293 5414574 2639199 1311149. Average 13351263 10921750 7966989 5391239 2667964 1333416. SD 102929.1 48370.26 46213.17 20341.26 24977.49 19353.36. Table: 2 succinic acid standard table showing area under the curve, averages, standard deviations and relative standard deviations.. 19. RSD 0.0077 0.0044 0.0058 0.0038 0.00936 0.0145. %RSD 0.77 0.44 0.58 0.38 0.93 1.4.

(21) Theoretical value 5 4 3 2 1 0.5. Actual value 5.0006 4.00048 3.00036 2.00024 1.00012 0.50006. Run1. Run 2. Run 3. AUC 1037475 835068.1 635299 432182.6 217934.3 110692.7. AUC 1022215 819678.3 631916 435565.9 215161 111065.1. AUC 1040812 815168.9 637510 434295.2 215651.2 111852.4. Average 1033501 823305.1 634908.3 434014.5 216248.8 111203.4. SD 9914.857 10433.59 2817.401 1709.026 1480.123 592.0717. RSD 0.0096 0.0126 0.0044 0.003937 0.00684 0.0053. Table: 3 urea standard table showing area under the curve, averages, standard deviations and relative standard deviations.. Figure: 11 urea-succinic acid standard graph. 20. %RSD 0.96 1.26 0.44 0.39 0.68 0.53.

(22) The solubility data obtained at a fixed stirring rate and different cooling rates showed that solubility of co-crystals was temperature dependent, it increases with increase in temperature and decreases with decrease in temperature as can be observed in the cooling profile figure 7. UREA Temp. 70 60 50 40 30 20 12. Run 1. Run2. Run3. Average. Area *10 320755.4 244764 132490.2 102473.8 68711.49 55097.15 47737.13. Area*10 382799.5 237268 114965.4 124968.9 65995.42 52533.28 43751.85. Area*10 323914.6 189358.3 121069.2 98628.53 67654.69 53796.51 48962.5. Area*10 342489.8 223796.8 122841.6 108690.4 67453.87 53808.98 46817.16. SD. RSD. 34944.93 30059.19 8895.822 14228.1 1369.126 1281.98 2724.422. 0.1 0.13 0.07 0.11 0.02 0.02 0.06. mg/ml *10 1.6 1.02 0.6 0.46 0.26 0.19 0.16. mg/ml 16 10.2 6 4.6 2.6 1.9 1.6. mol/liter 0.27 0.17 0.1 0.07 0.04 0.03 0.027. Table: 4 Urea solubility data. SA. Run 1. Run2. Run3. Temp. Area 10455190 10992078 7728430 7544974 6345903 6294752 6334004. Area 12684912 9447731 7735559 6917205 6531077 6201316 6451740. Area 10737016 9289092 7542692 7137401 6742271 6234201 6601487. 70 60 50 40 30 20 12. Average. 11292373 9909634 7668894 7199860 6539750 6243423 6462410. Table:5 Succinic acid solubility data. 21. SD. 1214179 940774.4 109351.7 318511 198326.3 47395.78 134060.2. RSD. 0.1 0.09 0.014 0.04 0.03 0.008 0.21. Conc mg/ml 4.18 3.69 2.86 2.68 2.45 2.33 2.4. mg/ml*10 41.8 36.9 28.6 26.8 24.5 23.3 24. mol/liter 0.35 0.31 0.24 0.23 0.21 0.2 0.2.

(23) Urea Succinic acid Solubility Graph 0.4 solubility mol/L. 0.35 0.3 0.25 0.2 0.15 0.1. Urea Succinic Acid. 0.05 0 0. 10. 20. 30. 40 50 Temperature. 60. 70. 80. Figure: 12 Urea-succinic acid solubility data.. 4.1.2.2 SCALE-UP OF CO-CRYSTALS Results obtained from DSC,PXRD and Raman spectroscopy confirmed the formation of co-crystals of urea-succinic acid on scale-up at different temperatures, stirring rates and cooling rates as shown in Tables 6 and 7. Cooling rate at(100rpm) 5ºC/hour 10ºC/hour. Collection temperature 15ºC 12ºC. Products Co-crystals Co-crystals. Table:6 Co-crystal formation at 100rpm with different temperatures and cooling rates. Cooling rate(150rpm) Collection temperature Products 5ºC/hour 15ºC Co-crystals 10ºC/hour 12ºC Co-crystals Table:7 Co-crystal formation at150rpm with different temperatures and cooling rates.. 22.

(24) 5.0 CONCLUSIONS The screening stage of urea-succinic acid co-crystal solubility indicated isopropanol as the most suitable solvent for crystallization process. This is because urea and succinic acid were more soluble in isopropanol than other organic solvents used in screening. The urea-succinic acid products obtained on small scale were investigated by DSC,PXRD and Raman spectroscopy. It was found that a urea-succinic acid co-crystal was formed , DSC indicated the melting point of urea at135.3°Cand melting point of succinic acid at 188.9°C and the melting point of the co-crystals 149.9°C and co-crystal results were distinctly different from both urea and succinic acid single crystals. This indicates that a new compound was formed with its distinct melting point and different physicochemical properties from its original components. The solubility curve of urea-succinic acid showed that succinic acid was more soluble than urea at a particular temperature. The solubility profile of urea-succinic co-crystal showed the temperature dependence of the process, the solubility decreases as the temperature decreases. Scale-up results obtained from DSC, PXRD, and Raman spectroscopy confirmed the formation and stability of co-crystal at different process parameters. Therefore we can conclude that the processing parameters like stirring rate, temperature, cooling rates have no significant influence on the quality of urea-succinic acid co-crystal obtained on scale-up.. 23.

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