Title of Invention	A PROCESS FOR PREPARING DENSE, CRYSTALLIZED AND SPHERICAL IBUPROFEN AGGLOMERATES
Abstract	A process for preparing dense, crystallized and spherical ibuprofen agglomerates having improved processing characteristics including gradual enhanced drug dissolution characteristic from non-spherical ibuprofen particles.

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FIELD OF INVENTION The present invention relates to a process for preparing dense, crystallized and spherical agglomerates having improved processing characteristics including gradual enhanced drug dissolution characteristic as shown herein table 1A, from non-spherical ibuprofen said process comprising the steps of: a. dissolving non-spherical ibuprofen particles in a first solvent to obtain an ibuprofen solution; b. mixing 40 to 85 % w/v of a non-solvent such as herein described with 10 to 30 % w/v of the ibuprofen solution of step (a) maintained at a temperature below about 10°C and heating the mixture at a temperature up to 50°C in the presence of 5 to 30 % w/v of a bridging liquid to obtain a slurry; c. stirring the slurry obtained in step (b) for a period in the range 10 to 60 minutes, and d. obtaining the dense, crystallized and spherical ibuprofen agglomerates by solvent change method. BACKGROUND AND PRIOR ART OF THE INVENTION Spherical crystallization is a novel particulate design technique to improve both the processability, such as mixing, filling, and tableting characteristics, and the bioavailability of pharmaceuticals. The spherical crystallization process is a multiple unit process in which crystallization, agglomeration and spheronization can be carried out simultaneously in one step. The resultant crystals can be designated as spherical agglomerates. Due to the characteristic shape, the micromeritic properties such as flowability, packability and compressibility of the resultant crystals are dramatically improved, so that direct tableting or coating is possible without further processing (mixing, agglomeration, sieving, etc.). The poor dissolution rate of Tolbutamide after modification by spherical crystallization in the presence of carboxy methyl cellulose sodium was shown by Ma-s; Li-ST; Liu-Q Kawashima -Y has described the effect of direct spherical agglomerations of drug crystals accompanied with and without polymorphism, solvation or complexation, during crystallization or reaction. Metoclopramide micro pellets were prepared in liquid phase by spherical crystallization technique and investigated by Xu -J; Pine-QN; Liu-GJ. Results showed that the micro pellets had a fine appearance and had less divergence in content of metoclopramide either in different batches of products or in the same batch of products with different particle sizes. Kawashima -Y Cui-F; Takeuchi-H;Niwa-T; Kiuchi-K et-al concluded that agitation speed is the main parameter determining the diameter of agglomerated crystals of acebutol. The principle of agglomeration was initially applied to coal and minerals. Owing to the naturally hydrophobic properties of coals, they agglomerate with ease and separate from the ash constituents by applying virtually any mode of agitation in the presence of sufficient hydrocarbons as bridging liquids. But the process cannot achieve commercialization due to high cost of the bridging oils. Since 1980 spherical crystallization has been studied as a size enlargement operation in the field of pharmacy. Finely divided solids in liquid suspension can be agglomerated and separated from the suspending liquid by the addition of a small amount of bridging liquid, which preferentially wets the surface of the solid. Thus surface properties of the crystals and nature of the bridging liquid play an important role in the agglomeration process. Barium sulphate in benzene provides hydrophilic surface, which is preferentially wetted and agglomerated using bridging liquid of polar nature like water. Bos et. al has studied the change in agglomerate size with time using light - scattering technique. Bemer et. al further proposed four regions in growth of agglomerates, as follows: i. Flocculation Zone: Where pendular bridges form loose opens floes of particles, ii. Zero - Growth zone - Loose floes get transformed into tightly packed pellets during which the entrapped suspension fluid is squeezed out followed by squeezing of bridging liquid onto the surface of small floes causing pore space in the pellet to be completely filled with the bridging liquid. The driving force for this transformation is provided by the agitation of the slurry causing liquid turbulence, pellet - pellet and pellet - stirrer collision. iii. Fast - Growth Zone: The fast growth of the agglomerate takes place when sufficient bridging liquid has squeezed out to the surface of small agglomerates, iv. Constant - Size Zone: In this zone the agglomerates cease to grow, or even shows slight decrease in size. Here the frequency of coalescence is balanced by the breakage frequency of agglomerates. The rate - determining step in the agglomeration growth occurs in zero - growth zone when the bringing liquid is squeezed out of the pores as the initial floes are transformed into small agglomerates. Another view proposes that the rate - determining step is the collision of particles with the bridging liquid droplets prior to the formation of liquid bridges. This rate is governed by the rate of agitation. The strength of agglomerate is determined by, interfacial tension between the bridging liquid and the continuous suspending liquid phase: contact angle and the ratio of the volumes of bridging liquid and solid particles. Capes and Suther land reported that the size of agglomerate is determined by the balance of the cohesive force of the particles composing the agglomerate and destruction force exerted on the agglomerate during agglomeration. Agitation speed and the mass of the agglomerate represent the main destructive force. Agglomeration behavior of five different samples of lactose in size range of 31 - 261 |im with chloroform as a bridging liquid, has shown that the agglomerate increases with increase in bridging liquid except at high primary particle size i.e. 261 |im. Porosity of the agglomerates increase with increase in particle size of lactose due to the weaker cohesive forces than in case for fine particles. Capes and Kawashima suggested that spherical agglomeration is a first order process whereas Vanagaamundi and Rao proposed it to be second order. The main requirement in the spherical crystallization system is that, it should provide a small amount of bridging liquid. The proportion of bridging liquid in the given system can be determined by plotting a ternary or solubility diagram of the bridging liquid in the given system. In the region above the phase separation curve, the system is completely miscible, but in the region just below the separation curve will provide small quantity of bridging liquid. 1. Simple Spherical Crystallization Method The process involves formation of fine crystals and their agglomeration. Crystallization is generally achieved by change of solvent or salting out. The solution of the material in a "good solvent" is poured in a "poor solvent" under controlled conditions, so as to favour formation of fine crystals. Agitating the crystals in a liquid suspension and adding a "bridging liquid" which preferentially wets the crystal surface to cause binding forms the agglomerates. The agglomerate may be spherical if the amount of this bridging liquid and the rate of agitation is controlled. Kawashima et. alf, carried out crystallization of salicylic acid by change of solvent, ethanol as good solvent and water as a poor solvent. The crystals were agglomerated using chloroform as a bridging liquid. Sodium theophylline was crystallized by sailing out from the solution of theophylline in aqueous ethylenediamine solution by addition of equal volume of (15% w/v) sodium chloride solution. The agglomerate crystals were produced by addition of adequate amount of ethanol and chloroform. 2. Emulsion Solvent Diffusion Method By this method, spherical crystallization can be carried out using a mixed system of two or three partially miscible solvents, i.e. bridging liquid - poor solvent system or good solvent -bridging liquid - poor solvent system. When bridging liquid (or plus good solvent) solution of the drug was poured into poor solvent (dispersing medium) under agitation, quasi emulsion droplets of bridging liquid or good solvent from the emulsion droplet into the dispersing medium induced the crystallization of the drug, followed by agglomeration. Antirheumatic drug Bucillamine was crystallized as spheres by emulsion solvent diffusion method using hydroxy Propyl methyl- cellulose for coating, uniformly coated directly compressible crystal agglomerates were obtained. 3. Ammonia Diffusion System, Method (A D S* method) Kawashima et.al developed a novel method for spherical crystallization of amphoteric drug substances. They carried out spherical crystallization of Enoxacin, an antibacterial, which is slightly soluble in water but soluble in acidic and alkaline solution. A mixture of three partially immiscible solvents i.e. acetone - ammonia water - dichloromethane was used as a crystallization system. In this system ammonia water acted as a bridging liquid as well as a good solvent for Enoxacin. Acetone is a water miscible but a poor solvent, thus Enoxacin gets precipitated by solvent change without forming ammonium salt. Water immiscible solvents such as hydrocarbons or halogenated hydrocarbons e.g. dichloromethane induced liberation of the ammonia water. Thus acetone in the solvent enter into droplets of ammonia water which are liberated from acetone-ammonia water- dichloromethane system, and consequently enoxacin dissolved in water is precipitated while the droplets collect the crystals. At the same time ammonia in the agglomerates diffuses to the outer organic solvent phase and it's ability as a bridging liquid becomes weaker and the agglomerates are obtained. This technique is termed as 'A D S' and is useful in agglomeration of drugs which are soluble only in an acidic or an alkaline solution. Ibuprofen is a Propionic acid derivative, non-steroidal anti-inflammatory, analgesic and antipyretic agent. It is an acidic compound with PKa value 5.3 greatly affected by changes in PH and therefore its absorption is PH dependent. It better absorbed from acidic conditions of stomach (PH In addition, Material intended for compression in to a tablet must possess two essential characteristics fluidity and compressibility. Hence it is desirable to have material in physical form, which would flow smoothly and uniformly. The ideal physical form for this purpose is a sphere, since they offer minimum contact surfaces between themselves and with walls of the machine parts. This led us to consider the preparation of spherical crystals of ibuprofen. Spherical crystallization technique has been described in present invention is very effective technique in improving the dissolution behavior of some drugs that are characterized by low water solubility and slow dissolution profiles. The technique has also been successfully utilized for improvement of flowability and compressibility of crystalline drugs. The aim of present investigation is to obtain spherical agglomerates of ibuprofen with improved pharmaceutical properties such as flowability, mechanical strength, dissolution rate and Bioavailability. OBJECT THE INVENTION The main object of the present invention is to obtain spherical, dense and crystallized ibuprofen agglomerates remarkably improved in flowability, packability and suitable for a direct tableting method not using an additive during the process for preparing the spherical, dense crystallized ibuprofen agglomerates. Another object of the invention is to reduce the amount of fines and promotes the crystallization of spherical, dense ibuprofen having diameter more than 770 micrometers. SUMMARY OF THE INVENTION The fine spherical particles are obtained by dissolving ibuprofen powder in a first solvent (Iso Propyl alcohol) and subsequently dropping the solution in a non-solvent solvent preferably water at a lower temperature than that of the first solvent, with stirring, in presence of a bridging solvent, capable of being dissolved in both the solvents. STATEMENT OF THE INVENTION 1. A process for preparing dense, crystallized and spherical ibuprofen agglomerates having improved processing characteristics including gradual enhanced drug dissolution characteristic as shown in table 1A, from non-spherical ibuprofen particles, said process comprising the steps of: a. dissolving non-spherical ibuprofen particles in a first solvent to obtain an ibuprofen solution; b. mixing 40 to 85 % w/v of a non-solvent such as herein described with 10 to 30 % w/v of the ibuprofen solution of step (a) maintained at a temperature below about 10°C and heating the mixture at a temperature up to 50°C in the presence of 5 to 30 % w/v of abridging liquid to obtain a slurry; c. stirring the slurry obtained in step (b) for a period in the range 10 to 60 minutes, and d. obtaining the dense, crystallized and spherical ibuprofen agglomerates by solvent change method. BRIEF DESCRIPTION OF TABLES: TABLE 1 show results of the experiments corresponding to ternary diagram. TABLE 2 show derived properties of spherical crystals in comparison with commercial sample. TABLE 3 showing dissolution profile of ibuprofen spherical crystals compared to commercial Sample And Re-Crystallized Sample (Uspxxi Model, Type-Ii) TABLE 4 depicting X-Ray diffraction patterns of ibuprofen commercial sample for d- spacing calculations. TABLE 5 showing ray diffraction patterns of re crystallized ibuprofen sample for d-spacing calculations. TABLE 6 showing X-ray diffraction patterns of ibuprofen spherical agglomerates sample for d- spacing calculations. DETAILED DESCRIPTION OF THE INVENTION (step by step description of the invention): Accordingly, the present invention relates to a process for preparing dense, crystallized and spherical ibuprofen agglomerates having improved processing characteristics including gradual enhanced drug dissolution characteristic as shown herein table 1A, from non-spherical ibuprofen particles, said process comprising the steps of: a. dissolving non-spherical ibuprofen particles in a first solvent to obtain an ibuprofen solution; b. mixing 40 to 85 % w/v of a non-solvent such as herein described with 10 to 30% w/v of the ibuprofen solution of step (a) maintained at a temperature below about 10°C and heating the mixture at a temperature up to 50°C in the presence of 5 to 30 % w/v of a bridging liquid to obtain a slurry; c. stirring the slurry obtained in step (b) for a period in the range 10 to 60 minutes and d. obtaining the dense, crystallized and spherical ibuprofen agglomerates by solvent change method. Yet another embodiment of the present invention relates to a process, wherein first solvent is selected from the group comprising of Isopropyl alcohol, sodium hydroxide, Acetone, methanol, ethanol, 2-propanol, tetrahydrofiiran. In yet another embodiment of the present invention relates to a process, wherein first solvent is Isopropyl alcohol. In another embodiment of the present invention relates to a process, wherein the Isopropyl alcohol used in the range of 40 to 80% w/v and more preferably 67.5% w/v. In another embodiment of the present invention relates to a process, wherein the no-solventor solvent is water or dilute hydrochloric acid. In another embodiment of the present invention, dilute hydrochloric used has normality of about 0.07N. In another embodiment of the present invention relates to a process, wherein the bridging liquid used is isopropyl acetate. Yet another embodiment of the present invention relates to a process wherein in step (c), solution stirring is carried out in the range of 300 to 700 rpm, preferably carried out at 500 rpm for time period of 25 to 45 min. Yet another embodiment of the present invention relates to a process wherein,'the ratio of ibuprofen solution to water to isopropyl acetate is about 21.875: about 71.8: about 6.25. Yet another embodiment of the present invention relates to a spherical, dense and crystallized ibuprofen agglomerates having average particle size in the range of 150 to 1204 jam, bulk density in the range of 0.205 to 0.490 gm/ml, effective dissolution time more than 30 minute and angle of repose is less than 23 to 29 degree. Further embodiment of the present invention relates a spherical, dense and crystallized ibuprofen agglomerates having average particle size of 770 jam, bulk density 0.46284 gm/sec, effective dissolution time more than 30 minute and angle of repose is less than 20 degree. There are several methods described for Spherical crystallization. One of the methods involves three solvent systems. Liquid I is solvent (S) for the drug and other being the non-solvent (NS) and the third liquid used is bridging solvent. The drug solution is added to an emulsion of non-solvent and bridging solvent under continuous stirring. The drug precipitates and crystallizes as spherical agglomerates. Preparation of spherical crystals: a) Choice of the liquid media The drug exhibits good solubility in several solvents (Acetone, methanol, ethanol, 2- propanol, tetrahydrofuran, etc). It is necessary to select solvent in which drug exhibits the best solubility as a very concentrated solution of drug could increase the densification of the material during crystallization process. b) Selection of the best liquid proportions The ternary diagram was built to find the best percentage of the three liquids 20 points were identified on the triangle. The optimal ratio for spherical crystals is found and proportions were then chosen. Particle characterization: Particle shape of Ibuprofen; Particle shape of ibuprofen commercial sample, re-crystallized sample and spherical crystals were observed using Scanning electron microscopy The Scanning electron microscopic photographs obtained to identify distinct morphological differences in the morphological modifications of the crystals among the samples. Particle size of Ibuprofen: Particle size of Ibuprofen commercial sample and re crystallized sample determined by measuring mean diameter under optical microscope and sieve analysis is carried out to determine mean diameter for the spherical crystals. Micromeritic properties Determination of apparent bulk density: Apparent bulk density is determined by pouring the samples i.e. commercial sample, re crystallized sample and spherical agglomerates in bulk in to a graduated cylinder. Tapped density is determined by placing a graduated cylinder containing a known mass of powder on a mechanical tapper apparatus (Electro lab-tap density tester). Samples are tapped until no further reduction in volume of the sample observed. Results are shown in table (2) Angle of repose (8) determination: The flow characteristics are measured by angle of repose. Improper flow of powder is due to frictional forces between the particles. These frictional forces are quantified by angle of repose. Angle of repose is defined as the maximum angle possible between the surface of the pile of the powder and the horizontal plane. To determine fixed funnel method is employed in which a funnel secured with its tip at a given height above the graph paper and placed on a flat horizontal surface. Powder or agglomerates is carefully poured through the funnel until the apex of the conical pile just touches the tip of the funnel. The radius and height of the pile were then determined. The angle of repose (0) for the samples was calculated. By definition tan0 = h/r h= height of pile and r= radius of the base of the pile 9= tan"lh/r radius Granule strength: Attrition method is used to determine the strength of spherical aggregates. Roche friabilator is charged with spherical crystals (6 gms) and then rotated for 100 revolutions. After four minutes of this treatment, crystals were weighed and compared to their initial weight. The percentage loss of mass for particular size is the usual value that represents the granule friability analysis. POWDER FLOW ABILITY AND COMPRESSIBILITY: Specific volume is determined by pouring a known mass of spherical crystals in to graduated cylinder. The volume is read off the cylinder and specific volume is calculated by dividing the volume of the mass of granules. At the same time the compressibility of a blend can also be determined. The graduated cylinder is vibrated on a shaker for a time period. This vibration reduces the volume that the blend occupies in the graduated cylinder. The percentage compressibility (Carr's index) is calculated The incorporation of Polyethylene Glycol during the preparation of Ibuprofen provides wide range of solubility and compatibility, which are useful in Pharmaceutical and cosmetic preparation. The Inventors have incorporated PEG to impart mechanical strength to the spherical agglomerates /crystal and to study its effect on dissolution characteristics of Ibuprofen. The inventors found various advantages of incorporation of PEG, which are herein mentioned 1) Increase in the PEG concentration significantly increased the mechanical strength of agglomerates. 2) Size of the agglomerates and percentage yield of the agglomerates decreases with increase in concentration of the PEG, due to the decrease of movements of agglomerated crystals in the medium. 3) Increase in viscosity would reduce the collision frequency of agglomerates in the vessel. 4) Higher concentration of PEG (15 %) probably absorbed on the crystals and prevented the crystal growth. 5) Reduction in the angle of repose with increase in the PEG concentration is due to the reduction in the inter-particle friction. DISSOLUTION STUDY The dissolution of ibuprofen commercial sample, re-crystallized sample and spherical crystals was determined by using USP dissolution apparatus-II (paddle method). The dissolution medium, according to the monograph of ibuprofen in USP, is a PH 7.4 Phosphate buffer. 5 ml of dissolution medium were withdrawn every 10 min over 60 min. The amount of dissolved drug was determined using UV Spectrophotometeric method (UV 1205 Shimadzu, Japan) at 221nm. The results are mean of three experiments. As it can be seen from table - 3 and figure - 3 that the dissolution profiles of commercial sample, re-crystallized ibuprofen and spherical crystals show significant difference after 30 minutes. Dissolution time should be lesser for the pharmaceutical solid dosage forms. Compendial or pharmacopoeial (Indian pharmacopoeia- IP) requirement is that at least 75% of solid drug should have been dissolved at the end of 30 th to 45th minute. If it is less than this specification drug or dosage does not qualify for conventional oral dosage form. Material being hydrophobic in nature and further reduction in effective surface for spherical crystals resulted in poor dissolution rates and profile. The study on dissolution characteristics of Ibuprofen by incorporation of Polyethylene Glycol is represented in Table-3A and Figure-3A. X-ray powder diffraction: Crystal X-ray scattering measurements are performed using Fea radiation (a=1.934A) and a scan speed 4 per minute. Diffraction pattern was analyzed using multi dimension minimization programme. The programme helps to calculate 2G values and cell parameters a, b, c, a, P and y which will fit the observed reflections to less than 5% of the mean value. No polymorphic changes are detected using X-ray diffraction (Fig-4). Diffraction angles are similar for both re-crystallized and spherical agglomerates. All the samples exhibited spectra with similar peak position (20 values). Therefore, the presence of different polymorphs of ibuprofen is ruled out. Only reflection intensities are increased for spherical crystals. All the crystal of ibuprofen commercial sample or re-crystallized sample or spherical agglomerated have the same crystal structure orthorhombic P222, which is the shape of ibuprofen crystal. The data obtained for commercial sample, re-crystallized and spherical agglomerates are reported in the table (4), (5) and (6). Powder Bed Hydrophilicity: To explain the differences observed in dissolution profiles, a wettability test was carried out using a very simple device. Ibuprofen 500mg commercial sample, re-crystallized sample and then spherical crystals were placed on a sintered glass disk forming the bottom of a glass tube. The whole device is brought in to contact with water and adjusted at 1mm under the surface of the water. Few methylene blue crystals were put on the surface of the drug. The time taken for the capillary rising of water to the surface was noted. This time is visualized by the dissolution of methylene blue crystals, which color the powder surface intensively. The shortest rising time would correspond to the most hydrophilic substance leading to good wettability. Materials used in the invention are Micronized Ibuprofen, Isopropyl alcohol (Analytical grade), Isopropyl acetate (Analytical grade).Materials were used as they were procured. BRIEF DESCRIPTION OF THE ACCOMPANYING DRAWINGS: FIGURE 1 # Equipment used in the process is shown. FIGURE 2 # Standard graph of Ibuprofen in Phosphate buffer PH 7.2 FIGURE 3 # Dissolution profile in pH 7.4Phosphate Buffer FIGURE 3 A # Comparative dissolution profile of ibuprofen FIGURE 4 # SEM Photograph of Ibuprofen commercial/pure sample FIGURE 5 # SEM Photograph of ibuprofen re crystallized sample FIGURE 6 # SEM photograph of Ibuprofen spherical crystals FIGURE 7 # SEM Photograph of Ibuprofen in presence of PEG ADVANTAGES OF THE INVENTION L One advantage, therefore, of the method of the present invention is that it reduces the amount of fines and promotes the crystallization of ibuprofen as dense spherical agglomerates, which are greater than 770 micrometers in diameter. These spheres can be readily washed free of the mother liquor without an undue loss of the final product. 2. Spherical, dense and crystallized ibuprofen exhibit remarkably improved in flowability and packability and suitable for a direct tableting method not using an additive. WE CLAIM: 1. A process for preparing dense, crystallized and spherical ibuprofen agglomerates having improved processing characteristics including gradual enhanced drug dissolution characteristic as shown in table 1 A, from non-spherical ibuprofen particles, said process comprising the steps of: e. dissolving non-spherical ibuprofen particles in a first solvent to obtain an ibuprofen solution; f. mixing 40 to 85 % w/v of a non-solvent such as herein described with 10 to 30 % w/v of the ibuprofen solution of step (a) maintained at a temperature below about 10°C and heating the mixture at a temperature up to 50°C in the presence of 5 to 30 % w/v of a bridging liquid to obtain a slurry; g. stirring the slurry obtained in step (b) for a period in the range 10 to 60 minutes, and h. obtaining the dense, crystallized and spherical ibuprofen agglomerates by solvent change method. 2. A process as claimed in claim 1 wherein in step (a), first solvent is selected from the group comprising of isopropyl alcohol, sodium hydroxide, Acetone, methanol, ethanol, 2-propanol, and tetrahydrofuran. 3. A process as claimed in claim 2, wherein the first solvent is isopropyl alcohol. 4. A process as claimed in claim 3, wherein the amount of isopropyl alcohol used is in the range of 40 to 80% w/v. 5. A process as claimed in claim 4, wherein the amount of isopropyl alcohol used is 67.5% w/v. 6. A process as claimed in claim 1, wherein the no-solvent used is water or dilute hydrochloric acid. 7. A process as claimed in claim 5, wherein the dilute hydrochloric acid used has normality of about 0.07N. 8. A process as claimed in claim 1, wherein the bridging liquid used is isopropyl acetate. 9. A process as claimed in claim 1 wherein in step (c), the slurry is stirred at a speed in the range of 300 to 700 rpm for time period in the range of 25 to 45 minute. 10. A process as claimed in claim 1 wherein in step (c), the slurry is stirred at a speed in the range of 500 rpm for time period of 30 min. 11. A process as claimed in claim 1, wherein the ratio of ibuprofen solution to water to isopropyl acetate is about 21.875: about 71.85 about 6.25. 12. A spherical, dense and crystallized ibuprofen agglomerates having average particle size in the range of 150 to 1204 jam, bulk density in the range of 0.205 to 0.490 gm/ml, effective dissolution time more than 30 minute and angle of repose is less than 23 to 29 degree. 13. A spherical, dense and crystallized as claimed in claim 1, wherein the agglomerates posses average particle size of 770 jam, bulk density 0.46284 gm/sec, effective dissolution time more than 30 minute and angle of repose is less than 20 degree. 14. A process for preparing dense, substantially as herein described with reference to the accompanying drawings. 15. A spherical, substantially as herein described with reference to the accompanying drawings.

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