Title of Invention	A PROCESS OF MAKING POROUS BIOACTIVE SCAFFOLDS, POROUS BONE FILLER MATERIALS, NANO SIZED CALCIUM HYDROXYI APATITE POWDER OR A COMPOSITE WITH OTHER CALCIUM PHOSPHATES
Abstract	The process of making nano-sized calcium hydroxy apatite powder and its composite with P-Ca3 (PO4)2 (3-TCP) and other calcium phosphates through modified solution combustion synthesis using pure or mixed fuels has been disclosed. The phase pure nano-sized calcium hydroxy apatite and the composites comprised of a mixture of calcium hydroxy apatite, ß-tri-calcium phosphate and other phosphates. In accordance with this invention the resultant product obtained by modified solution combustion synthesis is fluffy foam like mass composed of isometric spherical particles of 20-150 nm size. The nano-sized calcium hydroxy apatite powder and its composite material can also be processed to yield a porous bioactive scaffold and bone filler materials.

Title of Invention

A PROCESS OF MAKING POROUS BIOACTIVE SCAFFOLDS, POROUS BONE FILLER MATERIALS, NANO SIZED CALCIUM HYDROXYI APATITE POWDER OR A COMPOSITE WITH OTHER CALCIUM PHOSPHATES

Abstract

The process of making nano-sized calcium hydroxy apatite powder and its composite with P-Ca3 (PO4)2 (3-TCP) and other calcium phosphates through modified solution combustion synthesis using pure or mixed fuels has been disclosed. The phase pure nano-sized calcium hydroxy apatite and the composites comprised of a mixture of calcium hydroxy apatite, ß-tri-calcium phosphate and other phosphates. In accordance with this invention the resultant product obtained by modified solution combustion synthesis is fluffy foam like mass composed of isometric spherical particles of 20-150 nm size. The nano-sized calcium hydroxy apatite powder and its composite material can also be processed to yield a porous bioactive scaffold and bone filler materials.

Full Text	FIELD OF THE INVENTION The present invention relates to a process of making porous bioactive scaffolds and porous bone filler materials with nano sized calcium hydroxyapatite powder or a composite with other calcium phosphates. This invention particularly relates to a simple, cost-effective, energy efficient process for making nano-sized calcium hydroxy apatite powders by solution combustion synthesis technique. BACKGROUND OF THE INVENTION The human bone and teeth are mineralized tissues. A typical wet cortical bone is composed of 22wt% organic matrix, 69wt% mineral, and 9wt% water. The major sub phase of the mineral consists of submicroscopic crystals of an apatite of calcium and phosphate, whose crystal structure is very similar to calcium hydroxyl apatite. These crystals are slender needles, 20-40 nm long and 1.5 -7 nm in diameter. The mineral phase is made of a continuous cellular structure which gives very good mechanical strength. Ceramics are historically the oldest of the synthetic materials and their medical application can be traced back to ancient Egyptian periods. In Egyptian sarcophagi, both filled and artificial teeth have been found in the mouths of the mummies. The repair and reconstruction of osseous defects have long been a serious challenge to the skills of orthopedic and maxillofacial surgeons In order to restore form and function to patients, repairing bone defects presently involves several surgical techniques. However, although effective in many cases, the existing technology has numerous difficulties and disadvantages. Therefore the implantation of materials of different types in the human or animal body in order to replace bone portions which have been traumatized or which have deteriorated due to diseases is steadily increasing. In order to eliminate the risk of having immunological or infectious diseases and to avoid operations on several sites, different synthetic materials have come into use within this technical field. As examples of suitable materials used for said purpose there can be mentioned minerals and ceramics such as tri-calcium phosphate and calcium aluminate. Especially preferred materials are, however, materials having a chemical composition and crystal structure similar to those of the materials that are built up by the living organism, such as calcium hydroxy-apatite. One synthetic material of this type which has come into use for restoring bone tissue is the mineral calcium hydroxy apatite having chemical formula Ca10 (PO4)6(OH)2 and is available both as blocks of different shapes and granules of different sizes. Commercial hydroxyl apatite is supplied by many producers. Thus, for instance, hydroxy apatite of the above-mentioned composition is manufactured by Asahi Optical Co.. Ltd., Tokyo, Japan, Interpore Int. Irvine, Calif., USA, and Impladent Ltd., Holliswood, N.Y., USA. The material is available both as resorbable and as non-resorable hydroxy apatite granules/particles for different applications. PRIOR ART Reference may be made to United States Patent No.6231607 and W097/23428, by Ben Bassat wherein it is reported that a mixture of calcium ions, phosphate ions, aspartic acid and carbonate ions was exposed to microwave irradiation followed by quenching to room temperature, filtering with water and the resultant cake is pulverized, pressed and sintered to yield a mixture of calcium hydroxy apatite, α-and ß- tetra-calcium phosphates in different proportions which is useful as a bone graft substitute. The drawbacks of the process are the product is not pure calcium hydroxy apatite and the process is complex involving multiple steps. Reference may be made to patent no EP1110908 by Isobe Tetsuhiko et al wherein it was reported a method of synthesis of calcium hydroxy apatite by preparing a mixed material slurry by dispersing calcium hydroxide powder into a phosphoric acid solution; conducting a mechanochemical milling treatment in which shearing force and compressive force based on a centrifugal force of a mechanical rotating body are imparted to the mixed material slurry, and reacting the calcium hydrate component with the phosphoric acid component under normal temperature and pressure thereby to prepare calcium hydroxyl apatite powder having fine crystals with uniform particle size. The main drawbacks of the process are that the process is not very simple, time consuming and not very cost effective. Reference may be made to Korean Patent No. KR 9504767 by Lee Byong-Min et al in the reported synthesis of calcium hydroxy apatite using pre-saturated calcium hydroxide suspension solutions with aqueous phosphoric acid at a pH of 11.0. The drawbacks are that the process is not very simple, time consuming and not very cost effective. Reference may be made to French patent FR 2696439 by Jean-Claude Heughebaert discloses one method and apparatus for continuous production of calcium hydroxyl apatite powders from calcium salt solutions and aqueous phosphates at pH range of 6.0-7.0. The drawbacks are this process disclosed details of instrumentation only. Reference may be made to Canadian patent CN1391904 by Li Jinghong synthesis of calcium hydroxyl apatite in the size range of 5-800nm although the product contains 5 to 80% calcium hydroxy apatite and along with vitamins and other ingredients can be used for calcium supplementing agents. The drawbacks are that the product although ultra fine is not pure and crystalline and application is limited. Reference may be made to Canadian patent no CN1404880 by Sun Jiaju wherein a novel porous calcium carbonate-calcium hydroxy apatite gradient material is reported. In this product of different ratio surface layer is calcium hydroxyl apatite and the core is calcium carbonate. The drawbacks are that the product although ultra fine is not pure and crystalline and application is limited. Reference may be made to United States Patent No.7169372 by Rudin et al wherein a crystalline calcium hydroxy apatite synthesis involving multiple stages using multiple reactors is reported. The drawbacks are it involves too many stages and many reactors making the process difficult. Reference may be made to patent no. WO/2005/123579 by Kjellin et al. wherein a process of making nano sized calcium hydroxy apatite powder and very thin coating on titanium is described by using micro-emulsion technique. The drawbacks are it involves too many stages and time consuming making the process uneconomical. Reference may be made to patent no WO/2008/007992 by Lopes et. al wherein, a process of continuous synthesis of nano and micro sized calcium hydroxy apatite powder is described. The drawbacks are it involves too many controlling parameters and the primary product requires further processing through many stages making the process difficult. However, no prior art is reported on synthesis of pure nanosized calcium hydroxy apatites by solution combustion technique. Drawbacks of the above prior arts may be summarized as: 1 The products are not always pure. 2. The processes are complex involving multiple steps and multiple controlling parameters, time consuming and sometimes involves energy inefficient processing steps like sintering, pulverizing, milling etc. 3. In some cases products are not crystalline. The existing processes for synthesis of calcium hydroxyl apatite (Hap) are not simple and versatile. Known Hap powders are not always pure in composition and in some cases not crystalline. Moreover, in most of the cases, the particle size of the powders are not very fine, therefore, it can not be used to fabricate mechanically strong porous scaffolds and the range of applications are limited. A simple versatile process for synthesis of pure nano sized calcium hydroxyl apatite or a composite with other calcium phosphates is necessary. OBJECT OF THE PRESENT INVENTION The main object of the present invention is to provide a process of making nanosized calcium hydroxy apatite powder or a composite with other calcium phosphates which obviates the drawbacks of the hitherto known prior art as detailed above. Yet another object of the present invention is to provide an energy efficient process of making nano-sized calcium hydroxy apatite powder. Still another object of the present invention is to make the process of making nanosized calcium hydroxy apatite powder simpler. Yet another object of the present invention is to provide an economically favored process of making nano-sized calcium hydroxy apatite powder at lower temperature. Yet another object of the present invention is to provide a process of making phase pure nano-sized calcium hydroxy apatite powder using inferior grade raw materials (L. R. Grade chemicals). Still another object of the present invention is to make a composite of nano-sized calcium hydroxy apatite and (3-Tri-calcium phosphate or other calcium phosphates. Yet another object of the present invention is to provide a nano-sized calcium hydroxy apatite powder which can be processed to free flowing porous granules to be used as a bone graft material and can be used to treat damage to tissues in the dental cavity. Yet another object of the present invention is to provide a nano-sized calcium hydroxy apatite powder which can be processed to a porous scaffold with controlled porosity and can be used for orthopedic tissue engineering applications. SUMMARY OF THE PRESENT INVENTION Accordingly, the present invention provides a process of making porous bioactive scaffolds with nano sized calcium hydroxy apatite powder or a composite with other calcium phosphates and porous bioactive bone filler material comprising the steps of: a) mixing 0.5 to 2.75 molar aqueous solution of calcium nitrate with 0.5 to 5.5 molar aqueous solution of di-ammonium hydrogen phosphate; b) maintaining Ca:P molar ratio in the range of 1.45 to 1.76 to obtain the white precipitate; c) dissolving white precipitate as obtained in step (b) by adding concentrated 0.0 to 3.0 ml of nitric acid drop wise and to maintain the PH of the solution in the range of 3.0 to 3.5 with stirring followed by adding solid fuels comprising urea or glycine or a mixture of them in the proportion of 1.0 to 7.0 moles per mole of calcium, as such or in combination with glucose, dextrose or sucrose in the proportion of 0.0 to 1.0 moles per mole of calcium to obtain a mixture; d) stirring the mixture as obtained in step (c) to homogenize followed by heating the entire mixture in a controlled atmosphere in a furnace pre-heated at a temperature in the range of 500 to 700°C till the material swelled completely to yield a foam; e) igniting the swelled mass to obtain fluffy foam like mass. In an embodiment of the present invention the di-ammonium hydrogen phosphate is replaced by materials such as ammonium di hydrogen phosphate, phosphorous pentoxide or phosphoric acid. In yet another embodiment of the present invention the calcium nitrate may be replaced by a dilute nitric acid solution of calcium carbonate, calcium oxide and other calcium salts. In yet another embodiment of the present invention the glucose may be replaced by dextrose or sucrose or any other equivalent sugar compound. In still another embodiment homogenization refer to dissolution of solid fuels like urea, glycine, glucose, sucrose, dextrose or a mixture thereof in the system. In yet another embodiment of the present invention the ambient atmosphere may be replaced by suitable oxidizing, neutral or inert environment like flowing oxygen, nitrogen or argon. In yet another embodiment of the present invention a process of making porous bone grafting scaffold materials using nano hydroxyapatite powder comprising the steps of: a) milling of nanosized hydroxyapatite powder to a micro fine (-325 mesh) powder: b) mixing powder as obtained in step (a) thoroughly with ß-napthalene powder (≤296 Mm) in a ratio of about 53:47 wt% in geometrical fashion under controlled environment, cold iso-statically to obtain a mixture; c) pressing a mixture as obtained in step (b) in a silicone mold under 120 to 170 MPa pressure; d) heating the mold as obtained in step (c) in an air oven with an ascending series of temperatures (from room temperature to 90°C with a gradient of 10°C increment per stage), e) sintering the mold at 700 to 750°C for 0.2 to 2 minutes to obtain porous bioactive scaffold; f) cutting the scaffold as obtained in step (e) in required dimension and shape. In still another embodiment of the present invention of a process of making porous bone filler materials which comprises controlled grinding of porous bioceramic calcium hydroxyapatite or its composite (with other calcium phosphate) scaffolds and sieving to produce a coarse powder (0.5 to 1.5 mm) grains for use as bone filler materials. DETAILED DESCRIPTION The present invention describes a technique of solution combustion synthesis of nano-sized calcium hydroxy apatite powders in which aqueous Ca-nitrate, (or dilute nitric acid solution of suitable calcium salts), di-ammonium hydrogen ortho-phosphate (or other phosphate sources) system containing a single or mixture of fuels, is employed in order to obtain a homogeneous, porous, easily dispersible, nano-crystalline powder of calcium hydroxy apatite by using a mixture of suitable proportion of reactant fuels in required ratio and suitably controlling the reaction temperature, reaction environment and other processing parameters. The novelty of this invention is that the resultant calcium hydroxy apatite powder is nano-crystalline and does not require any further heat treatment. Further by controlling one or two parameters it is possible to change the nature and quality of the end product with very good precision. Thus the non-obvious inventive step of the present invention lies in utilizing solution combustion synthesis technology for the preparation of the novel materials i.e., nano-sized calcium hydroxy apatite and its composite with ß-tri-calcium phosphate or other calcium phosphates Another significant non-obvious point in this invention is that a mixture of fuels (urea, glycine and glucose) may be used for synthesis of pure nano-crystalline calcium hydroxy apatite or a composite with ß-tri-calcium phosphate or tetra calcium phosphate with reduced particle size compared with conventional combustion synthesized product. Another significant point in this invention is that laboratory grade reagents or chemicals may be used for synthesis of pure nano-crystalline calcium hydroxy apatite or a composite with tetra calcium phosphate. Another significant non-obvious point in this invention is that reaction atmosphere may be controlled for synthesis of controlled composition of the end product. Although the concentration of the reactant solutions does not affect the reaction kinetics of the combustion synthesis reaction very dilute solutions take longer time to evaporate out the solvent thus making the process time consuming and less energy efficient. The reaction temperature (temperature of the pre-heated furnace) influences the total reaction time but not the product crystal phases. However, increasing reaction temperature increases agglomeration of the resultant product powder. 1. The reactants calcium nitrate tetra-hydrate or dilute nitric acid solution of calcium carbonate, calcium oxide or any suitable calcium salt and di-ammonium hydrogen phosphate, or ammonium di-hydrogen phosphate, or phosphoric acid was dissolved in de-carbonated distilled water to make 0.5 to 2.75 molar and 0.5 to 5.5 molar aqueous solutions respectively. 2. The above said aqueous solutions are mixed in a Pyrex beaker of large size or in a glass lined vessel in predetermined appropriate volumes to maintain Ca:P molar ratio from 1.45 to 1.76 when a white precipitate formed. 3. Concentrated nitric acid is added drop-wise to the mixture with stirring till the pH changes close to 3.5 and the solution became transparent. 4. Solid fuel (urea, glycine in pure form or in a mixture of both) is added to the solution in 1 to 7 molar times with respect to the calcium nitrate concentration. 5. An additional fuel of sugar (glucose, dextrose or sucrose) is added to the solution in 0 to 1 molar times with respect to the calcium nitrate concentration. 6. The solution is homogenized by stirring. 7. The solution is placed in a controlled atmosphere in a furnace pre-heated to 500 to 700°C±5°C. 8. The solution boiled underwent dehydration, decomposed with evolution of large volume of gases. 9. The resultant mass then frothed and swelled to yield foam, a flame appeared and produced incandescence for about a minute. 10. The resultant soft voluminous fluffy foam like mass grounded manually to the desired product. 11. The nanosized calcium hydroxyapatite or its composite (with other calcium phosphate) powder of this invention can advantageously be used to form free flowing porous granules to be used as a bone graft material and can be used to treat damage to tissues in the dental cavity. 12. The finely ground hydroxyapatite powder or its composite (with other calcium phosphate) is mixed with a pore former like naphthalene (0 to 60% by weight) and pressed uniaxially to form pellets. The pellets are heat treated slowly at a suitable heat treatment schedule at ambient pressure and atmosphere or vacuum for a prolonged time to ensure complete drying. The resultant pellets are sintered at a suitable temperature (700 to 750°C) in an ambient atmosphere to result a porous scaffold. The porous scaffold on further controlled grinding results porous granules for application as bone filler. The present invention has main usages in medical science. In advanced surgical techniques particularly in the preparation of artificial bone or bone graft substitutes and in the area of biopharmaceutics, calcium hydroxy apatite is used for the development of effective implantable vehicles for drug delivery applications. It is also used as a coating either in pure form or in combination with other materials like bioactive glass or other calcium phosphates on metallic orthopaedic implants. Some calcium phosphates are considered biomaterials, used as: food additives and nutritional supplements; bone graft materials for bone replacement, growth and repair; biocements and coating of metallic implants. Some of the most recent applications include their use in cosmetics, toothpaste and in esthetical treatments for diminishing wrinkles by stimulating conjunctive tissue formation. The non-medical applications include packing media for column chromatography, gas sensors, various catalysts and host material for lasers. All percentages are expressed in weight percent unless otherwise specified. When the composition in this invention described herein states "about" it is contemplated that the values given are valid +/- 0.1 wt%. The following examples are given by way of illustration of the working of the invention in actual practice and should not be construed to limit the scope of the present invention in any way. EXAMPLE-1 40.85 gms of Ca(NO3)2-4H2O, dissolved in 100 ml of decarbonated distilled water to make 1.73 molar aqueous solution, 21.52 gms of di-ammonium hydrogen phosphate dissolved in 100 ml of decarbonated distilled water to make 1.63 molar aqueous solution. 21.54 ml of Ca (NO3)2.4H2O solution and 13.01 ml of di-ammonium hydrogen phosphate solution were mixed in a 250 ml Pyrex beaker to obtain a Ca:P molar ratio of 1.76. Immediately a white precipitate formed. The resulting white precipitate was dissolved by adding 3.0 ml of concentrated nitric acid dropwise with stirring. 14 gms of solid urea (0.233mole) was added to it and the mixture was homogenized by stirring for 30 minutes at room temperature. The beaker was heated in ambient atmosphere in a furnace preheated at 580°C. The solution soon started to boil, underwent dehydration and decomposition and a large volume of gases evolved. The resulting mass then frothed and swelled to yield foam, where a flame appeared and produced incandescence. The resulting product is voluminous, fluffy foam like mass. The resultant powder is mixed thoroughly with ß-napthalene powder (≤296 µm) in a ratio of about 53:47 wt% in geometrical fashion under controlled environment cold iso-statically pressed, dried carefully in a controlled manner and finally sintered at 700°C for 2 minutes and cut to required dimension and shape of the bone grafting scaffolds. The product is characterized by X-ray to study the phase formation (Philips Analytical, X'Pert, 1830, Holland), I. R. spectroscopy in the range of 4000 Cm-1 to 400 Cm-1 by Fourier Transform Infra-Red (FTIR) spectrometer (Perkin-Elmer, Model 1615) in the transmission mode. The median diameter of the resultant powder particles and the particle size distribution were ascertained by photon correlation spectroscopy (Mastersizer 2000, Malvern, UK).The particle morphology, agglomerate structure and the microstructure were investigated using a scanning electron microscope (SEM) (Leo430i). The XRD analysis showed the product as pure crystalline calcium hydroxy apatite. FTIR spectrum corroborates the XRD data. Particle size analysis and SEM micrograph results indicate the product is nano-sized agglomerated powder composed of 60-150 nm diameter isometric spherical particles. EXAMPLE-2 40.85 gms of Ca(NO3)2-4H2O, dissolved in 100 ml of decarbonated distilled water to make 1.73 molar aqueous solution, 21.52 gms of di-ammonium hydrogen phosphate dissolved in 100 ml of decarbonated distilled water to make 1.63 molar aqueous solution. 21.54 ml of Ca(NO3)2-4H2O solution and 13.66 ml of di-ammonium hydrogen phosphate solution were mixed in a 250 ml pyrex beaker to obtain a Ca:P molar ratio of 1.67. Immediately a white precipitate formed. The resulting white precipitate was dissolved by adding 3.0 ml of concentrated nitric acid dropwise with stirring. 7.00 gms of solid urea (0.1165 mole) and 8.74 gms of solid glycine (0.1165 mole) was added to it and the mixture was homogenized by stirring for 30 minutes at room temperature. The beaker was heated in ambient atmosphere in a furnace preheated at 600°C. The solution soon started to boil, underwent dehydration and decomposition and a large volume of gases evolved. The resulting mass then frothed and swelled to yield foam, where a flame appeared and produced incandescence. The resulting product is voluminous, fluffy foam like mass. The resultant powder is mixed thoroughly with ß-napthalene powder (≤296 µm) in a ratio of about 53:47 wt% in geometrical fashion under controlled environment, cold iso-statically pressed, dried carefully in a controlled manner and finally sintered at 750°C for 0.2 minutes and further milled and sieved to yield a desired particle size (1.0 mm to 1.5 mm) powder for subsequent use as bone filler material. The XRD analysis showed the product contains crystalline calcium hydroxy apatite and (3-tri-calcium phosphate (15 vol%). FTIR spectrum corroborates the XRD data. Particle size analysis and SEM micrograph results indicate the product is nano-sized agglomerated powder composed of 70-100 nm diameter isometric spherical particles. EXAMPLE-3 40.85 gms of Ca(NO3)2.4H2O, dissolved in 100 ml of decarbonated distilled water to make 1.73 molar aqueous solution, 21.52 gms of di-ammonium hydrogen phosphate dissolved in 100 ml of decarbonated distilled water to make 1.63 molar aqueous solution. 21.54 ml of Ca(NO3)2.4H2O solution and 15.75 ml of di-ammonium hydrogen phosphate solution were mixed in a 250 ml pyrex beaker to obtain a Ca.P molar ratio of 1.45. Immediately a white precipitate formed. The resulting white precipitate was dissolved by adding 3.0 ml of concentrated nitric acid dropwise with stirring. 14 gms of solid urea (0.233mole) was added to it and the mixture was homogenized by stirring for 30 minutes at room temperature. The beaker was heated in ambient atmosphere in a furnace preheated at 620°C. The solution soon started to boil, underwent dehydration and decomposition and a large volume of gases evolved. The resulting mass then frothed and swelled to yield foam, where a flame appeared and produced incandescence. The resulting product is voluminous, fluffy foam like mass. The resultant powder is mixed thoroughly with ß-napthalene powder (≤296 µm) in a ratio of about 53:47 wt% in geometrical fashion under controlled environment, cold iso-statically pressed, dried carefully in a controlled manner and finally sintered at 725°C for 20 seconds and cut to required dimension and shape of the bone grafting scaffolds The XRD analysis showed the product contains crystalline calcium hydroxy apatite as minor phase ß-tri-calcium phosphate and α-tri-calcium phosphate as major constituent. FTIR spectrum corroborates the XRD data. Particle size analysis and SEM micrograph results indicate the product is nano-sized agglomerated powder composed of 60-130 nm diameter isometric spherical particles. EXAMPLE-4 64.94 gms of Ca(NO3)2.4H2O, dissolved in 100 ml of decarbonated distilled water to make 2.75 molar aqueous solution, 72.6 gms of di-ammonium hydrogen phosphate dissolved in 100 ml of decarbonated distilled water to make 5.5 molar aqueous solution. 13.55 ml of Ca(NO3)2.4H2O solution and 3.86 ml of di-ammonium hydrogen phosphate solution were mixed in a 250 ml pyrex beaker to obtain a Ca:P molar ratio of 1.76. Immediately a white precipitate formed. The resulting white precipitate was dissolved by adding 3 0 ml of concentrated nitric acid dropwise with stirring. An aqueous solution of 19.50 gms of solid glycine (0.26 mole) was added to it and the mixture was homogenized by stirring for 30 minutes at room temperature. The solution was further concentrated to a small volume by evaporation at 80 to 100°C and then transferred to a glass lined reactor vessel. The vessel was heated under flowing nitrogen or argon atmosphere in a tube furnace preheated at 550°C. The solution soon started to boil, underwent dehydration and decomposition and a large volume of gases evolved. The resulting mass then frothed and swelled to yield foam, where no flame appeared. The resulting product is slightly gray or blackish voluminous, fluffy foam like mass. The resultant powder is mixed thoroughly with ß-napthalene powder (≤296 µm) in a ratio of about 53:47 wt% in geometrical fashion under controlled environment, cold iso-statically pressed, dried carefully in a controlled manner and finally sintered at 700 C for 1.0 minutes and cut to required dimension and shape of the bone grafting scaffolds The XRD analysis showed the product as pure crystalline calcium hydroxy apatite. FTIR spectrum corroborates the XRD data. Particle size analysis and SEM micrograph results indicate the product is nano-sized agglomerated powder composed of isometric spherical particles. EXAMPLE-5 11.81 gms of Ca(NO3)2.4H2O, dissolved in 100 ml of decarbonated distilled water to make 0.5 molar aqueous solution, 72.6 gms of di-ammonium hydrogen phosphate dissolved in 100 ml of decarbonated distilled water to make 5.5 molar aqueous solution. 74.5 ml of Ca(NO3)2-4H2O solution and 3.86 ml of di-ammonium hydrogen phosphate solution were mixed in a 250 ml pyrex beaker to obtain a Ca:P molar ratio of 1.76. Immediately a white precipitate formed. The resulting white precipitate was dissolved by adding 3.0 ml of concentrated nitric acid dropwise with stirring. 11.18 gms of solid urea (0.19 mole) and 0.43 gms of glucose or dextrose (0.0024 mole) was added to it and the mixture was homogenized by stirring for 30 minutes at room temperature. The beaker was heated in ambient atmosphere in a furnace preheated at 700°C. The solution soon started to boil, underwent dehydration and decomposition and a large volume of gases evolved. The resulting mass then frothed and swelled to yield a foam, which smolder for a couple of minutes without any flame. The resulting product is voluminous, fluffy foam like mass. The resultant powder is mixed thoroughly with ß-napthalene powder (≤296 µm) in a ratio of about 53:47 wt% in geometrical fashion under controlled environment, cold iso-statically pressed, dried carefully in a controlled manner and finally sintered at 720°C for 0.5 minutes and further milled and sieved to yield a desired particle size (1.0 mm to 1.5 mm) powder for subsequent use as bone filler material. The XRD analysis showed the product as composite of crystalline calcium hydroxy apatite and other phosphates. FTIR spectrum corroborates the XRD data. Particle size analysis and SEM micrograph results indicate the product is nano-sized (20-100 nm) agglomerated powder composed of isometric spherical particles. EXAMPLE-6 17.30 gms of CaCO3 or 9.69 gms of CaO, dissolved in 100 ml of very dilute nitric acid solution to make 1.73 molar aqueous solution, 6.6 gms of di-ammonium hydrogen phosphate dissolved in 100 ml of decarbonated distilled water to make 0.5 molar aqueous solution. 21.54 ml of Ca(NO3)2.4H2O solution and 42.42 ml of di-ammonium hydrogen phosphate solution were mixed in a 250 ml pyrex beaker to obtain a Ca:P molar ratio of 1.76. Sometimes, a white precipitate formed. The resulting white precipitate was dissolved by adding 3.0 ml of concentrated nitric acid dropwise with stirring. 14 gms of solid urea (0.233mole) was added to it and the mixture was homogenized by stirring for 30 minutes at room temperature. The beaker was heated in ambient atmosphere in a furnace preheated at 650°C. The solution soon started to boil, underwent dehydration and decomposition and a large volume of gases evolved. The resulting mass then frothed and swelled to yield foam, where a flame appeared and produced incandescence. The resulting product is voluminous, fluffy foam like mass. The XRD analysis showed the product as composite of crystalline calcium hydroxy apatite and other phosphates. FTIR spectrum corroborates the XRD data. Particle size analysis and SEM micrograph results indicate the product is nano-sized agglomerated powder composed of isometric spherical particles. EXAMPLE-7 40.85 gms of Ca(NO3)2.4H2O, dissolved in 100 ml of decarbonated distilled water to make 1.73 molar aqueous solution, 18.75 gms of ammonium di-hydrogen phosphate dissolved in 100 ml of decarbonated distilled water to make 1.63 molar aqueous solution. 21.54 ml of Ca(NO3)2.4H2O solution and 13.66 ml of ammonium di-hydrogen phosphate solution were mixed in a 250 ml pyrex beaker to obtain a Ca:P molar ratio of 1.67. Immediately a white precipitate formed. The resulting white precipitate was dissolved by adding 3.0 ml of concentrated nitric acid dropwise with stirring. 14 gms of solid urea (0.233mole) was added to it and the mixture was homogenized by stirring for 30 minutes at room temperature. The beaker was heated in ambient atmosphere in a furnace preheated at 600°C. The solution soon started to boil, underwent dehydration and decomposition and a large volume of gases evolved. The resulting mass then frothed and swelled to yield a foam, where a flame appeared and produced incandescence. The resulting product is voluminous, fluffy foam like mass. The XRD analysis showed the product as composite of crystalline calcium hydroxy apatite and other phosphates. FTIR spectrum corroborates the XRD data. Particle size analysis and SEM micrograph results indicate the product is nano-sized agglomerated powder composed of isometric spherical particles. EXAMPLE-8 40.85 gms of Ca(NO3)2.4H2O, dissolved in 100 ml of decarbonated distilled water to make 1.73 molar aqueous solution, 21.54 ml of Ca(NO3)2.4H2O solution and 1.25 ml of concentrated phosphoric acid (laboratory reagent grade) in 5.0 ml of decarbonated distilled water were mixed in a 250 ml pyrex beaker to obtain a Ca:P molar ratio of 1.67. 14 gms of solid urea (0.233mole) was added to it and the mixture was homogenized by stirring for 30 minutes at room temperature The beaker was heated in ambient atmosphere in a furnace preheated at 600°C. The solution soon started to boil, underwent dehydration and decomposition and a large volume of gases evolved. The resulting mass then frothed and swelled to yield foam, where a flame appeared and produced incandescence. The resulting product is voluminous, fluffy foam like mass. EXAMPLE-9 64.23 gms of Ca(NO3)2.4H2O, dissolved in 100 ml of decarbonated distilled water to make 2.72 molar aqueous solution, 27.59 gms of di-ammonium hydrogen phosphate dissolved in 100 ml of decarbonated distilled water to make 2.09 molar aqueous solution. 32.2 ml of Ca(NO3)2.4H2O solution and 25.10 ml of di-ammonium hydrogen phosphate solution were mixed in a 250 ml pyrex beaker to obtain a Ca:P molar ratio of 1.67. Immediately a white precipitate formed. The resulting white precipitate was dissolved by adding 3.50 ml of concentrated nitric acid drop wise with stirring. 8.76 gms (0.146 mole) of solid urea was added to it and the mixture was homogenized by stirring for 30 minutes at room temperature. The beaker was heated in ambient atmosphere in a furnace preheated at 500°C. The solution soon started to boil, underwent dehydration and decomposition and a large volume of gases evolved. The resulting mass then frothed and swelled to yield a foam, where a flame appeared and produced incandescence. The resulting product is voluminous, fluffy foam like mass. EXAMPLE-10 64.23 gms of Ca(NO3)2.4H2O, dissolved in 100 ml of decarbonated distilled water to make 2.72 molar aqueous solution, 27.59 gms of di-ammonium hydrogen phosphate dissolved in 100 ml of decarbonated distilled water to make 2.09 molar aqueous solution. 32.2 ml of Ca (NO3)2-4H2O solution and 25.10 ml of di-ammonium hydrogen phosphate solution were mixed in a 250 ml pyrex beaker to obtain a Ca:P molar ratio of 1.67. Immediately a white precipitate formed. The resulting white precipitate was dissolved by adding 3.0 ml of concentrated nitric acid drop wise with stirring. 32.85 gms of solid urea or 40.2 gms of glycine (0.536 mole of fuel) was added to it and the mixture was homogenized by stirring for 30 minutes at room temperature. The beaker was heated in ambient atmosphere in a furnace preheated at 500°C. The solution soon started to boil, underwent dehydration and decomposition and a large volume of gases evolved. The resulting mass then frothed and swelled to yield a foam, where a flame appeared and produced incandescence. The resulting product is voluminous, fluffy foam like mass. The XRD analysis showed the product as composite of crystalline calcium hydroxy apatite and other phosphates. FTIR spectrum corroborates the XRD data. Particle size analysis and SEM micrograph results indicate the product is nano-sized agglomerated powder composed of isometric spherical particles. The products of all the examples cited above were characterized by X-ray to study the phase formation (Philips Analytical, X'Pert, 1830, Holland), I. R. spectroscopy in the range of 4000 Cm-1 to 400 Cm-1 by Fourier Transform Infra-Red (FTIR) spectrometer (Perkin-Elmer, Model 1615) in the transmission mode. The median diameter of the resultant powder particles and the particle size distribution were ascertained by photon correlation spectroscopy (Mastersizer 2000, Malvern, UK).The particle morphology, agglomerate structure and the microstructure were investigated using a scanning electron microscope (SEM) (Leo430i). The powders are all nano-crystalline and the size varies from 60 to 150 nm. The FTIR spectra of the samples showed characteristic PO4 bands at 1046, 954, 600 and 569 cm-1 and OH stretching mode at 3431 cm-1. The XRD patterns of the samples showed presence of desired calcium hydroxy apatite phase. However, depending upon the starting Ca.P molar ratio the product powder may contain other crystalline phases like ß-Ca3(PO4)2 (ß-TCP) and other tri-calcium phosphates in different proportions depending upon starting raw materials and starting molar ratio. The SEM micrographs taken showed that the particles are agglomerated and highly porous and composed of fine isometric particles having narrow size distribution. ADVANTAGES 1. Preparation of nano-sized calcium hydroxy apatite powder with narrow range of particle size distribution. 2. The present process provides a method of preparation of phase pure nano-sized calcium hydroxy apatite powders and its composite with ß-Ca3(PO4)2 (ß-TCP) at low temperature by an energy efficient simple process by using cheap laboratory grade reagents. 3. The present process provides a method of preparation of phase pure nano-sized calcium hydroxyl apatite powders and its composite with ß-Ca3(PO4)2 (ß-TCP) or other calcium phosphates with controlled particle size by using suitable combinations of different fuels and other processing parameters. 4. The present process provides a method of preparation of phase pure nano-sized calcium hydroxyl apatite powders and its composite with ß-Ca3(PO4)2 (ß-TCP) that can be used as bioactive porous scaffold 5. The present process provides a method of preparation of porous bone filler materials. We claim 1. A process of making nano sized calcium hydroxy apatite powder or a composite with other calcium phosphates useful as porous bioactive scaffolds and porous bone filler materials, comprising the steps of: a) mixing 0.5 to 2.75 molar aqueous solution of calcium nitrate with 0.5 to 5.5 molar aqueous solution of di-ammonium hydrogen phosphate; b) maintaining Ca:P molar ratio in the range of 1.45 to 1.76 to obtain the white precipitate; c) dissolving white precipitate as obtained in step (b) by adding concentrated 0.0 to 3.0 ml of nitric acid drop wise and to maintain the pH of the solution in the range of 3.0 to 3.5 with stirring followed by adding solid fuels comprising urea or glycine or a mixture of them in the proportion of 1.0 to 7.0 moles per mole of calcium, as such or in combination with glucose, dextrose or sucrose in the proportion of 0.0 to 1.0 moles per mole of calcium to obtain a mixture; d) stirring the mixture as obtained in step (c) to homogenize followed by heating the entire mixture in a controlled atmosphere in a furnace pre-heated at a temperature in the range of 500 to 700°C till the material swelled completely to yield a foam; e) igniting the swelled mass to obtain fluffy foam like mass. 2. A process as claimed in claiml wherein di-ammonium hydrogen phosphate is replaced by materials such as ammonium di-hydrogen phosphate, phosphoric acid. 3. A process as claimed in claiml wherein calcium nitrate is replaced with calcium carbonate or calcium oxide or any suitable calcium salts dissolved in very dilute nitric acid. 4. A process as claimed in claiml wherein homogenization refers to dissolution of solid fuels in the system. 5. A process as claimed in claim 1 wherein glucose may be replaced by dextrose or sucrose or any other equivalent sugar compound. 6. A process as claimed in claiml wherein the controlled atmosphere may be suitable oxidizing, neutral or inert environment like flowing oxygen, nitrogen or argon. 7. A process of making porous bone grafting scaffold materials using nano hydroxyapatite powder as claimed in claiml, comprising the steps of: a) milling of nanosized hydroxyapatite powder to a micro fine (-325 mesh) powder: b) mixing powder as obtained in step (a) thoroughly with ß-napthalene powder (≤296 urn) in a ratio of about 53:47 wt% in geometrical fashion under controlled environment, cold iso-statically to obtain a mixture; c) pressing a mixture as obtained in step (b) in a silicone mold under 120 to 170 MPa pressure; d) heating the mold as obtained in step (c) in an air oven with an ascending series of temperatures (from room temperature to 90°C with a gradient of 10°C increment per stage), e) sintering the mold at 700 to 750°C for 0.2 to 2 minutes to obtain bone grafting scaffold; f) cutting the scaffold as obtained in step (e) to required dimension and shape. 8. A process of making porous bone filler materials which comprises controlled grinding of porous bioceramic scaffolds and sieving to produce a coarse powder in the range of 0.5 to 1.5 mm grains for use as bone filler materials. 9. A process of making porous bioactive scaffolds, porous bone filler materials, nano sized calcium hydroxy apatite powder or a composite with other calcium phosphates substantially as herein described with reference to the examples.

Full Text

FIELD OF THE INVENTION
The present invention relates to a process of making porous bioactive scaffolds and porous bone filler materials with nano sized calcium hydroxyapatite powder or a composite with other calcium phosphates. This invention particularly relates to a simple, cost-effective, energy efficient process for making nano-sized calcium hydroxy apatite powders by solution combustion synthesis technique.
BACKGROUND OF THE INVENTION
The human bone and teeth are mineralized tissues. A typical wet cortical bone is composed of 22wt% organic matrix, 69wt% mineral, and 9wt% water. The major sub phase of the mineral consists of submicroscopic crystals of an apatite of calcium and phosphate, whose crystal structure is very similar to calcium hydroxyl apatite. These crystals are slender needles, 20-40 nm long and 1.5 -7 nm in diameter. The mineral phase is made of a continuous cellular structure which gives very good mechanical strength.
Ceramics are historically the oldest of the synthetic materials and their medical application can be traced back to ancient Egyptian periods. In Egyptian sarcophagi, both filled and artificial teeth have been found in the mouths of the mummies. The repair and reconstruction of osseous defects have long been a serious challenge to the skills of orthopedic and maxillofacial surgeons In order to restore form and function to patients, repairing bone defects presently involves several surgical techniques. However, although effective in many cases, the existing technology has numerous difficulties and disadvantages. Therefore the implantation of materials of different types in the human or animal body in order to replace bone portions which have been traumatized or which have deteriorated due to diseases is steadily increasing. In order to eliminate the risk of having immunological or infectious diseases and to avoid operations on several sites, different synthetic materials have come into use within this technical field. As examples of suitable materials used for said purpose there can be mentioned minerals and ceramics such as tri-calcium phosphate and calcium aluminate. Especially preferred materials are, however, materials having a chemical composition and crystal structure similar to those of the materials that are built up by the living organism, such as calcium hydroxy-apatite. One synthetic material of this type which has come into use for restoring bone tissue is the mineral calcium hydroxy apatite having chemical formula Ca10 (PO4)6(OH)2
and is available both as blocks of different shapes and granules of different sizes. Commercial hydroxyl apatite is supplied by many producers. Thus, for instance, hydroxy apatite of the above-mentioned composition is manufactured by Asahi Optical Co.. Ltd., Tokyo, Japan, Interpore Int. Irvine, Calif., USA, and Impladent Ltd., Holliswood, N.Y., USA. The material is available both as resorbable and as non-resorable hydroxy apatite granules/particles for different applications.
PRIOR ART
Reference may be made to United States Patent No.6231607 and W097/23428, by Ben Bassat wherein it is reported that a mixture of calcium ions, phosphate ions, aspartic acid and carbonate ions was exposed to microwave irradiation followed by quenching to room temperature, filtering with water and the resultant cake is pulverized, pressed and sintered to yield a mixture of calcium hydroxy apatite, α-and ß- tetra-calcium phosphates in different proportions which is useful as a bone graft substitute. The drawbacks of the process are the product is not pure calcium hydroxy apatite and the process is complex involving multiple steps.
Reference may be made to patent no EP1110908 by Isobe Tetsuhiko et al wherein it was reported a method of synthesis of calcium hydroxy apatite by preparing a mixed material slurry by dispersing calcium hydroxide powder into a phosphoric acid solution; conducting a mechanochemical milling treatment in which shearing force and compressive force based on a centrifugal force of a mechanical rotating body are imparted to the mixed material slurry, and reacting the calcium hydrate component with the phosphoric acid component under normal temperature and pressure thereby to prepare calcium hydroxyl apatite powder having fine crystals with uniform particle size. The main drawbacks of the process are that the process is not very simple, time consuming and not very cost effective.
Reference may be made to Korean Patent No. KR 9504767 by Lee Byong-Min et al in the reported synthesis of calcium hydroxy apatite using pre-saturated calcium hydroxide suspension solutions with aqueous phosphoric acid at a pH of 11.0. The drawbacks are that the process is not very simple, time consuming and not very cost effective.
Reference may be made to French patent FR 2696439 by Jean-Claude Heughebaert discloses one method and apparatus for continuous production of calcium hydroxyl apatite powders from calcium salt solutions and aqueous phosphates at pH range of 6.0-7.0. The drawbacks are this process disclosed details of instrumentation only.
Reference may be made to Canadian patent CN1391904 by Li Jinghong synthesis of calcium hydroxyl apatite in the size range of 5-800nm although the product contains 5 to 80% calcium hydroxy apatite and along with vitamins and other ingredients can be used for calcium supplementing agents. The drawbacks are that the product although ultra fine is not pure and crystalline and application is limited.
Reference may be made to Canadian patent no CN1404880 by Sun Jiaju wherein a novel porous calcium carbonate-calcium hydroxy apatite gradient material is reported. In this product of different ratio surface layer is calcium hydroxyl apatite and the core is calcium carbonate. The drawbacks are that the product although ultra fine is not pure and crystalline and application is limited.
Reference may be made to United States Patent No.7169372 by Rudin et al wherein a crystalline calcium hydroxy apatite synthesis involving multiple stages using multiple reactors is reported. The drawbacks are it involves too many stages and many reactors making the process difficult.
Reference may be made to patent no. WO/2005/123579 by Kjellin et al. wherein a process of making nano sized calcium hydroxy apatite powder and very thin coating on titanium is described by using micro-emulsion technique. The drawbacks are it involves too many stages and time consuming making the process uneconomical.
Reference may be made to patent no WO/2008/007992 by Lopes et. al wherein, a process of continuous synthesis of nano and micro sized calcium hydroxy apatite powder is described. The drawbacks are it involves too many controlling parameters and the primary product requires further processing through many stages making the process difficult.
However, no prior art is reported on synthesis of pure nanosized calcium hydroxy
apatites by solution combustion technique.
Drawbacks of the above prior arts may be summarized as:
1 The products are not always pure.
2. The processes are complex involving multiple steps and multiple controlling parameters, time consuming and sometimes involves energy inefficient processing steps like sintering, pulverizing, milling etc.
3. In some cases products are not crystalline.
The existing processes for synthesis of calcium hydroxyl apatite (Hap) are not simple and versatile. Known Hap powders are not always pure in composition and in some cases not crystalline. Moreover, in most of the cases, the particle size of the powders are not very fine, therefore, it can not be used to fabricate mechanically strong porous scaffolds and the range of applications are limited. A simple versatile process for synthesis of pure nano sized calcium hydroxyl apatite or a composite with other calcium phosphates is necessary.
OBJECT OF THE PRESENT INVENTION
The main object of the present invention is to provide a process of making nanosized calcium hydroxy apatite powder or a composite with other calcium phosphates which obviates the drawbacks of the hitherto known prior art as detailed above.
Yet another object of the present invention is to provide an energy efficient process of making nano-sized calcium hydroxy apatite powder.
Still another object of the present invention is to make the process of making nanosized calcium hydroxy apatite powder simpler.
Yet another object of the present invention is to provide an economically favored process of making nano-sized calcium hydroxy apatite powder at lower temperature.
Yet another object of the present invention is to provide a process of making phase pure nano-sized calcium hydroxy apatite powder using inferior grade raw materials (L. R. Grade chemicals).
Still another object of the present invention is to make a composite of nano-sized calcium hydroxy apatite and (3-Tri-calcium phosphate or other calcium phosphates.
Yet another object of the present invention is to provide a nano-sized calcium hydroxy apatite powder which can be processed to free flowing porous granules to be used as a bone graft material and can be used to treat damage to tissues in the dental cavity.
Yet another object of the present invention is to provide a nano-sized calcium hydroxy apatite powder which can be processed to a porous scaffold with controlled porosity and can be used for orthopedic tissue engineering applications.
SUMMARY OF THE PRESENT INVENTION
Accordingly, the present invention provides a process of making porous bioactive scaffolds with nano sized calcium hydroxy apatite powder or a composite with other calcium phosphates and porous bioactive bone filler material comprising the steps of:
a) mixing 0.5 to 2.75 molar aqueous solution of calcium nitrate with 0.5 to 5.5 molar
aqueous solution of di-ammonium hydrogen phosphate;
b) maintaining Ca:P molar ratio in the range of 1.45 to 1.76 to obtain the white precipitate;
c) dissolving white precipitate as obtained in step (b) by adding concentrated 0.0 to
3.0 ml of nitric acid drop wise and to maintain the PH of the solution in the range of 3.0 to 3.5 with stirring followed by adding solid fuels comprising urea or glycine or a mixture of them in the proportion of 1.0 to 7.0 moles per mole of calcium, as such or in combination with glucose, dextrose or sucrose in the proportion of 0.0 to 1.0 moles per mole of calcium to obtain a mixture;
d) stirring the mixture as obtained in step (c) to homogenize followed by heating the
entire mixture in a controlled atmosphere in a furnace pre-heated at a temperature in the range of 500 to 700°C till the material swelled completely to yield a foam;
e) igniting the swelled mass to obtain fluffy foam like mass.
In an embodiment of the present invention the di-ammonium hydrogen phosphate is replaced by materials such as ammonium di hydrogen phosphate, phosphorous pentoxide or phosphoric acid.
In yet another embodiment of the present invention the calcium nitrate may be replaced by a dilute nitric acid solution of calcium carbonate, calcium oxide and other calcium salts.
In yet another embodiment of the present invention the glucose may be replaced by dextrose or sucrose or any other equivalent sugar compound.
In still another embodiment homogenization refer to dissolution of solid fuels like urea, glycine, glucose, sucrose, dextrose or a mixture thereof in the system.
In yet another embodiment of the present invention the ambient atmosphere may be replaced by suitable oxidizing, neutral or inert environment like flowing oxygen, nitrogen or argon.
In yet another embodiment of the present invention a process of making porous bone grafting scaffold materials using nano hydroxyapatite powder comprising the steps of:
a) milling of nanosized hydroxyapatite powder to a micro fine (-325 mesh) powder:
b) mixing powder as obtained in step (a) thoroughly with ß-napthalene powder (≤296
Mm) in a ratio of about 53:47 wt% in geometrical fashion under controlled environment, cold iso-statically to obtain a mixture;
c) pressing a mixture as obtained in step (b) in a silicone mold under 120 to 170 MPa pressure;
d) heating the mold as obtained in step (c) in an air oven with an ascending series of temperatures (from room temperature to 90°C with a gradient of 10°C increment per stage),
e) sintering the mold at 700 to 750°C for 0.2 to 2 minutes to obtain porous bioactive scaffold;
f) cutting the scaffold as obtained in step (e) in required dimension and shape.
In still another embodiment of the present invention of a process of making porous bone filler materials which comprises controlled grinding of porous bioceramic calcium hydroxyapatite or its composite (with other calcium phosphate) scaffolds and sieving to produce a coarse powder (0.5 to 1.5 mm) grains for use as bone filler materials.
DETAILED DESCRIPTION
The present invention describes a technique of solution combustion synthesis of nano-sized calcium hydroxy apatite powders in which aqueous Ca-nitrate, (or dilute nitric acid solution of suitable calcium salts), di-ammonium hydrogen ortho-phosphate (or other phosphate sources) system containing a single or mixture of fuels, is employed in order to obtain a homogeneous, porous, easily dispersible, nano-crystalline powder of calcium hydroxy apatite by using a mixture of suitable proportion of reactant fuels in required ratio and suitably controlling the reaction temperature, reaction environment and other processing parameters. The novelty of this invention is that the resultant calcium hydroxy apatite powder is nano-crystalline and does not require any further heat treatment. Further by controlling one or two parameters it is possible to change the nature and quality of the end product with very good precision.
Thus the non-obvious inventive step of the present invention lies in utilizing solution combustion synthesis technology for the preparation of the novel materials i.e., nano-sized calcium hydroxy apatite and its composite with ß-tri-calcium phosphate or other calcium phosphates
Another significant non-obvious point in this invention is that a mixture of fuels (urea, glycine and glucose) may be used for synthesis of pure nano-crystalline calcium hydroxy apatite or a composite with ß-tri-calcium phosphate or tetra calcium phosphate with reduced particle size compared with conventional combustion synthesized product.
Another significant point in this invention is that laboratory grade reagents or chemicals may be used for synthesis of pure nano-crystalline calcium hydroxy apatite or a composite with tetra calcium phosphate.
Another significant non-obvious point in this invention is that reaction atmosphere may be controlled for synthesis of controlled composition of the end product.
Although the concentration of the reactant solutions does not affect the reaction kinetics of the combustion synthesis reaction very dilute solutions take longer time to evaporate out the solvent thus making the process time consuming and less energy efficient. The reaction temperature (temperature of the pre-heated furnace) influences the total reaction time but not the product crystal phases. However, increasing reaction temperature increases agglomeration of the resultant product powder.
1. The reactants calcium nitrate tetra-hydrate or dilute nitric acid solution of calcium carbonate, calcium oxide or any suitable calcium salt and di-ammonium hydrogen phosphate, or ammonium di-hydrogen phosphate, or phosphoric acid was dissolved in de-carbonated distilled water to make 0.5 to 2.75 molar and 0.5 to 5.5 molar aqueous solutions respectively.
2. The above said aqueous solutions are mixed in a Pyrex beaker of large size or in a glass lined vessel in predetermined appropriate volumes to maintain Ca:P molar ratio from 1.45 to 1.76 when a white precipitate formed.
3. Concentrated nitric acid is added drop-wise to the mixture with stirring till the pH changes close to 3.5 and the solution became transparent.
4. Solid fuel (urea, glycine in pure form or in a mixture of both) is added to the solution in 1 to 7 molar times with respect to the calcium nitrate concentration.
5. An additional fuel of sugar (glucose, dextrose or sucrose) is added to the solution in 0 to 1 molar times with respect to the calcium nitrate concentration.
6. The solution is homogenized by stirring.
7. The solution is placed in a controlled atmosphere in a furnace pre-heated to 500 to 700°C±5°C.
8. The solution boiled underwent dehydration, decomposed with evolution of large volume of gases.
9. The resultant mass then frothed and swelled to yield foam, a flame appeared and produced incandescence for about a minute.
10. The resultant soft voluminous fluffy foam like mass grounded manually to the desired product.
11. The nanosized calcium hydroxyapatite or its composite (with other calcium phosphate) powder of this invention can advantageously be used to form free flowing porous granules to be used as a bone graft material and can be used to treat damage to tissues in the dental cavity.
12. The finely ground hydroxyapatite powder or its composite (with other calcium phosphate) is mixed with a pore former like naphthalene (0 to 60% by weight) and pressed uniaxially to form pellets. The pellets are heat treated slowly at a suitable heat treatment schedule at ambient pressure and atmosphere or vacuum for a prolonged time to ensure complete drying. The resultant pellets are sintered at a suitable temperature (700 to 750°C) in an ambient atmosphere to result a porous scaffold. The porous scaffold on further controlled grinding results porous granules for application as bone filler.
The present invention has main usages in medical science. In advanced surgical techniques particularly in the preparation of artificial bone or bone graft substitutes and in the area of biopharmaceutics, calcium hydroxy apatite is used for the development of effective implantable vehicles for drug delivery applications. It is also used as a coating either in pure form or in combination with other materials like bioactive glass or other calcium phosphates on metallic orthopaedic implants. Some calcium phosphates are considered biomaterials, used as: food additives and nutritional supplements; bone graft materials for bone replacement, growth and repair; biocements and coating of metallic implants. Some of the most recent applications include their use in cosmetics, toothpaste and in esthetical treatments for diminishing wrinkles by stimulating conjunctive tissue formation. The non-medical applications include packing media for column chromatography, gas sensors, various catalysts and host material for lasers.
All percentages are expressed in weight percent unless otherwise specified. When the composition in this invention described herein states "about" it is contemplated that the values given are valid +/- 0.1 wt%.
The following examples are given by way of illustration of the working of the invention in actual practice and should not be construed to limit the scope of the present invention in any way. EXAMPLE-1
40.85 gms of Ca(NO3)2-4H2O, dissolved in 100 ml of decarbonated distilled water to make 1.73 molar aqueous solution, 21.52 gms of di-ammonium hydrogen phosphate dissolved in 100 ml of decarbonated distilled water to make 1.63 molar aqueous solution. 21.54 ml of Ca (NO3)2.4H2O solution and 13.01 ml of di-ammonium
hydrogen phosphate solution were mixed in a 250 ml Pyrex beaker to obtain a Ca:P molar ratio of 1.76. Immediately a white precipitate formed. The resulting white precipitate was dissolved by adding 3.0 ml of concentrated nitric acid dropwise with stirring. 14 gms of solid urea (0.233mole) was added to it and the mixture was homogenized by stirring for 30 minutes at room temperature. The beaker was heated in ambient atmosphere in a furnace preheated at 580°C. The solution soon started to boil, underwent dehydration and decomposition and a large volume of gases evolved. The resulting mass then frothed and swelled to yield foam, where a flame appeared and produced incandescence. The resulting product is voluminous, fluffy foam like mass.
The resultant powder is mixed thoroughly with ß-napthalene powder (≤296 µm) in a ratio of about 53:47 wt% in geometrical fashion under controlled environment cold iso-statically pressed, dried carefully in a controlled manner and finally sintered at 700°C for 2 minutes and cut to required dimension and shape of the bone grafting scaffolds.
The product is characterized by X-ray to study the phase formation (Philips Analytical, X'Pert, 1830, Holland), I. R. spectroscopy in the range of 4000 Cm-1 to 400 Cm-1 by Fourier Transform Infra-Red (FTIR) spectrometer (Perkin-Elmer, Model 1615) in the transmission mode. The median diameter of the resultant powder particles and the particle size distribution were ascertained by photon correlation spectroscopy (Mastersizer 2000, Malvern, UK).The particle morphology, agglomerate structure and the microstructure were investigated using a scanning electron microscope (SEM) (Leo430i).
The XRD analysis showed the product as pure crystalline calcium hydroxy apatite. FTIR spectrum corroborates the XRD data. Particle size analysis and SEM micrograph results indicate the product is nano-sized agglomerated powder composed of 60-150 nm diameter isometric spherical particles.
EXAMPLE-2
40.85 gms of Ca(NO3)2-4H2O, dissolved in 100 ml of decarbonated distilled water to make 1.73 molar aqueous solution, 21.52 gms of di-ammonium hydrogen phosphate dissolved in 100 ml of decarbonated distilled water to make 1.63 molar aqueous solution. 21.54 ml of Ca(NO3)2-4H2O solution and 13.66 ml of di-ammonium hydrogen phosphate solution were mixed in a 250 ml pyrex beaker to obtain a Ca:P
molar ratio of 1.67. Immediately a white precipitate formed. The resulting white precipitate was dissolved by adding 3.0 ml of concentrated nitric acid dropwise with stirring. 7.00 gms of solid urea (0.1165 mole) and 8.74 gms of solid glycine (0.1165 mole) was added to it and the mixture was homogenized by stirring for 30 minutes at room temperature. The beaker was heated in ambient atmosphere in a furnace preheated at 600°C. The solution soon started to boil, underwent dehydration and decomposition and a large volume of gases evolved. The resulting mass then frothed and swelled to yield foam, where a flame appeared and produced incandescence. The resulting product is voluminous, fluffy foam like mass. The resultant powder is mixed thoroughly with ß-napthalene powder (≤296 µm) in a ratio of about 53:47 wt% in geometrical fashion under controlled environment, cold iso-statically pressed, dried carefully in a controlled manner and finally sintered at 750°C for 0.2 minutes and further milled and sieved to yield a desired particle size (1.0 mm to 1.5 mm) powder for subsequent use as bone filler material. The XRD analysis showed the product contains crystalline calcium hydroxy apatite and (3-tri-calcium phosphate (15 vol%). FTIR spectrum corroborates the XRD data. Particle size analysis and SEM micrograph results indicate the product is nano-sized agglomerated powder composed of 70-100 nm diameter isometric spherical particles.
EXAMPLE-3
40.85 gms of Ca(NO3)2.4H2O, dissolved in 100 ml of decarbonated distilled water to make 1.73 molar aqueous solution, 21.52 gms of di-ammonium hydrogen phosphate dissolved in 100 ml of decarbonated distilled water to make 1.63 molar aqueous solution. 21.54 ml of Ca(NO3)2.4H2O solution and 15.75 ml of di-ammonium hydrogen phosphate solution were mixed in a 250 ml pyrex beaker to obtain a Ca.P molar ratio of 1.45. Immediately a white precipitate formed. The resulting white precipitate was dissolved by adding 3.0 ml of concentrated nitric acid dropwise with stirring. 14 gms of solid urea (0.233mole) was added to it and the mixture was homogenized by stirring for 30 minutes at room temperature. The beaker was heated in ambient atmosphere in a furnace preheated at 620°C. The solution soon started to boil, underwent dehydration and decomposition and a large volume of gases evolved. The resulting mass then frothed and swelled to yield foam, where a
flame appeared and produced incandescence. The resulting product is voluminous, fluffy foam like mass.
The resultant powder is mixed thoroughly with ß-napthalene powder (≤296 µm) in a ratio of about 53:47 wt% in geometrical fashion under controlled environment, cold iso-statically pressed, dried carefully in a controlled manner and finally sintered at 725°C for 20 seconds and cut to required dimension and shape of the bone grafting scaffolds
The XRD analysis showed the product contains crystalline calcium hydroxy apatite as minor phase ß-tri-calcium phosphate and α-tri-calcium phosphate as major constituent. FTIR spectrum corroborates the XRD data. Particle size analysis and SEM micrograph results indicate the product is nano-sized agglomerated powder composed of 60-130 nm diameter isometric spherical particles.
EXAMPLE-4
64.94 gms of Ca(NO3)2.4H2O, dissolved in 100 ml of decarbonated distilled water to make 2.75 molar aqueous solution, 72.6 gms of di-ammonium hydrogen phosphate dissolved in 100 ml of decarbonated distilled water to make 5.5 molar aqueous solution. 13.55 ml of Ca(NO3)2.4H2O solution and 3.86 ml of di-ammonium hydrogen phosphate solution were mixed in a 250 ml pyrex beaker to obtain a Ca:P molar ratio of 1.76. Immediately a white precipitate formed. The resulting white precipitate was dissolved by adding 3 0 ml of concentrated nitric acid dropwise with stirring. An aqueous solution of 19.50 gms of solid glycine (0.26 mole) was added to it and the mixture was homogenized by stirring for 30 minutes at room temperature. The solution was further concentrated to a small volume by evaporation at 80 to 100°C and then transferred to a glass lined reactor vessel. The vessel was heated under flowing nitrogen or argon atmosphere in a tube furnace preheated at 550°C. The solution soon started to boil, underwent dehydration and decomposition and a large volume of gases evolved. The resulting mass then frothed and swelled to yield foam, where no flame appeared. The resulting product is slightly gray or blackish voluminous, fluffy foam like mass.
The resultant powder is mixed thoroughly with ß-napthalene powder (≤296 µm) in a ratio of about 53:47 wt% in geometrical fashion under controlled environment, cold iso-statically pressed, dried carefully in a controlled manner and finally sintered at
700 C for 1.0 minutes and cut to required dimension and shape of the bone grafting
scaffolds
The XRD analysis showed the product as pure crystalline calcium hydroxy apatite.
FTIR spectrum corroborates the XRD data. Particle size analysis and SEM
micrograph results indicate the product is nano-sized agglomerated powder
composed of isometric spherical particles.
EXAMPLE-5
11.81 gms of Ca(NO3)2.4H2O, dissolved in 100 ml of decarbonated distilled water to make 0.5 molar aqueous solution, 72.6 gms of di-ammonium hydrogen phosphate dissolved in 100 ml of decarbonated distilled water to make 5.5 molar aqueous solution. 74.5 ml of Ca(NO3)2-4H2O solution and 3.86 ml of di-ammonium hydrogen phosphate solution were mixed in a 250 ml pyrex beaker to obtain a Ca:P molar ratio of 1.76. Immediately a white precipitate formed. The resulting white precipitate was dissolved by adding 3.0 ml of concentrated nitric acid dropwise with stirring. 11.18 gms of solid urea (0.19 mole) and 0.43 gms of glucose or dextrose (0.0024 mole) was added to it and the mixture was homogenized by stirring for 30 minutes at room temperature. The beaker was heated in ambient atmosphere in a furnace preheated at 700°C. The solution soon started to boil, underwent dehydration and decomposition and a large volume of gases evolved. The resulting mass then frothed and swelled to yield a foam, which smolder for a couple of minutes without any flame. The resulting product is voluminous, fluffy foam like mass. The resultant powder is mixed thoroughly with ß-napthalene powder (≤296 µm) in a ratio of about 53:47 wt% in geometrical fashion under controlled environment, cold iso-statically pressed, dried carefully in a controlled manner and finally sintered at 720°C for 0.5 minutes and further milled and sieved to yield a desired particle size (1.0 mm to 1.5 mm) powder for subsequent use as bone filler material. The XRD analysis showed the product as composite of crystalline calcium hydroxy apatite and other phosphates. FTIR spectrum corroborates the XRD data. Particle size analysis and SEM micrograph results indicate the product is nano-sized (20-100 nm) agglomerated powder composed of isometric spherical particles.
EXAMPLE-6
17.30 gms of CaCO3 or 9.69 gms of CaO, dissolved in 100 ml of very dilute nitric acid solution to make 1.73 molar aqueous solution, 6.6 gms of di-ammonium hydrogen phosphate dissolved in 100 ml of decarbonated distilled water to make 0.5 molar aqueous solution. 21.54 ml of Ca(NO3)2.4H2O solution and 42.42 ml of di-ammonium hydrogen phosphate solution were mixed in a 250 ml pyrex beaker to obtain a Ca:P molar ratio of 1.76. Sometimes, a white precipitate formed. The resulting white precipitate was dissolved by adding 3.0 ml of concentrated nitric acid dropwise with stirring. 14 gms of solid urea (0.233mole) was added to it and the mixture was homogenized by stirring for 30 minutes at room temperature. The beaker was heated in ambient atmosphere in a furnace preheated at 650°C. The solution soon started to boil, underwent dehydration and decomposition and a large volume of gases evolved. The resulting mass then frothed and swelled to yield foam, where a flame appeared and produced incandescence. The resulting product is voluminous, fluffy foam like mass.
The XRD analysis showed the product as composite of crystalline calcium hydroxy apatite and other phosphates. FTIR spectrum corroborates the XRD data. Particle size analysis and SEM micrograph results indicate the product is nano-sized agglomerated powder composed of isometric spherical particles.
EXAMPLE-7
40.85 gms of Ca(NO3)2.4H2O, dissolved in 100 ml of decarbonated distilled water to make 1.73 molar aqueous solution, 18.75 gms of ammonium di-hydrogen phosphate dissolved in 100 ml of decarbonated distilled water to make 1.63 molar aqueous solution. 21.54 ml of Ca(NO3)2.4H2O solution and 13.66 ml of ammonium di-hydrogen phosphate solution were mixed in a 250 ml pyrex beaker to obtain a Ca:P molar ratio of 1.67. Immediately a white precipitate formed. The resulting white precipitate was dissolved by adding 3.0 ml of concentrated nitric acid dropwise with stirring. 14 gms of solid urea (0.233mole) was added to it and the mixture was homogenized by stirring for 30 minutes at room temperature. The beaker was heated in ambient atmosphere in a furnace preheated at 600°C. The solution soon started to boil, underwent dehydration and decomposition and a large volume of gases evolved. The resulting mass then frothed and swelled to yield a foam, where a flame appeared and produced incandescence. The resulting product is voluminous, fluffy foam like mass.
The XRD analysis showed the product as composite of crystalline calcium hydroxy apatite and other phosphates. FTIR spectrum corroborates the XRD data. Particle size analysis and SEM micrograph results indicate the product is nano-sized agglomerated powder composed of isometric spherical particles.
EXAMPLE-8
40.85 gms of Ca(NO3)2.4H2O, dissolved in 100 ml of decarbonated distilled water to make 1.73 molar aqueous solution, 21.54 ml of Ca(NO3)2.4H2O solution and 1.25 ml of concentrated phosphoric acid (laboratory reagent grade) in 5.0 ml of decarbonated distilled water were mixed in a 250 ml pyrex beaker to obtain a Ca:P molar ratio of 1.67. 14 gms of solid urea (0.233mole) was added to it and the mixture was homogenized by stirring for 30 minutes at room temperature The beaker was heated in ambient atmosphere in a furnace preheated at 600°C. The solution soon started to boil, underwent dehydration and decomposition and a large volume of gases evolved. The resulting mass then frothed and swelled to yield foam, where a flame appeared and produced incandescence. The resulting product is voluminous, fluffy foam like mass.
EXAMPLE-9
64.23 gms of Ca(NO3)2.4H2O, dissolved in 100 ml of decarbonated distilled water to make 2.72 molar aqueous solution, 27.59 gms of di-ammonium hydrogen phosphate dissolved in 100 ml of decarbonated distilled water to make 2.09 molar aqueous solution. 32.2 ml of Ca(NO3)2.4H2O solution and 25.10 ml of di-ammonium hydrogen phosphate solution were mixed in a 250 ml pyrex beaker to obtain a Ca:P molar ratio of 1.67. Immediately a white precipitate formed. The resulting white precipitate was dissolved by adding 3.50 ml of concentrated nitric acid drop wise with stirring. 8.76 gms (0.146 mole) of solid urea was added to it and the mixture was homogenized by stirring for 30 minutes at room temperature. The beaker was heated in ambient atmosphere in a furnace preheated at 500°C. The solution soon started to boil, underwent dehydration and decomposition and a large volume of gases evolved. The resulting mass then frothed and swelled to yield a foam, where a flame appeared and produced incandescence. The resulting product is voluminous, fluffy foam like mass.
EXAMPLE-10
64.23 gms of Ca(NO3)2.4H2O, dissolved in 100 ml of decarbonated distilled water to make 2.72 molar aqueous solution, 27.59 gms of di-ammonium hydrogen phosphate dissolved in 100 ml of decarbonated distilled water to make 2.09 molar aqueous solution. 32.2 ml of Ca (NO3)2-4H2O solution and 25.10 ml of di-ammonium hydrogen phosphate solution were mixed in a 250 ml pyrex beaker to obtain a Ca:P molar ratio of 1.67. Immediately a white precipitate formed. The resulting white precipitate was dissolved by adding 3.0 ml of concentrated nitric acid drop wise with stirring. 32.85 gms of solid urea or 40.2 gms of glycine (0.536 mole of fuel) was added to it and the mixture was homogenized by stirring for 30 minutes at room temperature. The beaker was heated in ambient atmosphere in a furnace preheated at 500°C. The solution soon started to boil, underwent dehydration and decomposition and a large volume of gases evolved. The resulting mass then frothed and swelled to yield a foam, where a flame appeared and produced incandescence. The resulting product is voluminous, fluffy foam like mass. The XRD analysis showed the product as composite of crystalline calcium hydroxy apatite and other phosphates. FTIR spectrum corroborates the XRD data. Particle size analysis and SEM micrograph results indicate the product is nano-sized agglomerated powder composed of isometric spherical particles. The products of all the examples cited above were characterized by X-ray to study the phase formation (Philips Analytical, X'Pert, 1830, Holland), I. R. spectroscopy in the range of 4000 Cm-1 to 400 Cm-1 by Fourier Transform Infra-Red (FTIR) spectrometer (Perkin-Elmer, Model 1615) in the transmission mode. The median diameter of the resultant powder particles and the particle size distribution were ascertained by photon correlation spectroscopy (Mastersizer 2000, Malvern, UK).The particle morphology, agglomerate structure and the microstructure were investigated using a scanning electron microscope (SEM) (Leo430i). The powders are all nano-crystalline and the size varies from 60 to 150 nm. The FTIR spectra of the samples showed characteristic PO4 bands at 1046, 954, 600 and 569 cm-1 and OH stretching mode at 3431 cm-1. The XRD patterns of the samples showed presence of desired calcium hydroxy apatite phase. However, depending upon the starting Ca.P molar ratio the product powder may contain other crystalline phases like ß-Ca3(PO4)2 (ß-TCP) and other tri-calcium phosphates in different proportions depending upon starting raw materials and starting molar ratio.
The SEM micrographs taken showed that the particles are agglomerated and highly porous and composed of fine isometric particles having narrow size distribution.
ADVANTAGES
1. Preparation of nano-sized calcium hydroxy apatite powder with narrow range of particle size distribution.
2. The present process provides a method of preparation of phase pure nano-sized calcium hydroxy apatite powders and its composite with ß-Ca3(PO4)2 (ß-TCP) at low temperature by an energy efficient simple process by using cheap laboratory grade reagents.
3. The present process provides a method of preparation of phase pure nano-sized calcium hydroxyl apatite powders and its composite with ß-Ca3(PO4)2 (ß-TCP) or other calcium phosphates with controlled particle size by using suitable combinations of different fuels and other processing parameters.
4. The present process provides a method of preparation of phase pure nano-sized calcium hydroxyl apatite powders and its composite with ß-Ca3(PO4)2 (ß-TCP) that can be used as bioactive porous scaffold
5. The present process provides a method of preparation of porous bone filler materials.

We claim
1. A process of making nano sized calcium hydroxy apatite powder or a composite
with other calcium phosphates useful as porous bioactive scaffolds and porous bone
filler materials, comprising the steps of:
a) mixing 0.5 to 2.75 molar aqueous solution of calcium nitrate with 0.5 to 5.5 molar
aqueous solution of di-ammonium hydrogen phosphate;
b) maintaining Ca:P molar ratio in the range of 1.45 to 1.76 to obtain the white precipitate;
c) dissolving white precipitate as obtained in step (b) by adding concentrated 0.0 to
3.0 ml of nitric acid drop wise and to maintain the pH of the solution in the range of 3.0 to 3.5 with stirring followed by adding solid fuels comprising urea or glycine or a mixture of them in the proportion of 1.0 to 7.0 moles per mole of calcium, as such or in combination with glucose, dextrose or sucrose in the proportion of 0.0 to 1.0 moles per mole of calcium to obtain a mixture;
d) stirring the mixture as obtained in step (c) to homogenize followed by heating the
entire mixture in a controlled atmosphere in a furnace pre-heated at a temperature in the range of 500 to 700°C till the material swelled completely to yield a foam;
e) igniting the swelled mass to obtain fluffy foam like mass.
2. A process as claimed in claiml wherein di-ammonium hydrogen phosphate is replaced by materials such as ammonium di-hydrogen phosphate, phosphoric acid.
3. A process as claimed in claiml wherein calcium nitrate is replaced with calcium carbonate or calcium oxide or any suitable calcium salts dissolved in very dilute nitric acid.
4. A process as claimed in claiml wherein homogenization refers to dissolution of solid fuels in the system.
5. A process as claimed in claim 1 wherein glucose may be replaced by dextrose or sucrose or any other equivalent sugar compound.
6. A process as claimed in claiml wherein the controlled atmosphere may be
suitable oxidizing, neutral or inert environment like flowing oxygen, nitrogen or
argon.
7. A process of making porous bone grafting scaffold materials using nano
hydroxyapatite powder as claimed in claiml, comprising the steps of:
a) milling of nanosized hydroxyapatite powder to a micro fine (-325 mesh) powder:
b) mixing powder as obtained in step (a) thoroughly with ß-napthalene powder (≤296
urn) in a ratio of about 53:47 wt% in geometrical fashion under controlled environment, cold iso-statically to obtain a mixture;
c) pressing a mixture as obtained in step (b) in a silicone mold under 120 to 170
MPa pressure;
d) heating the mold as obtained in step (c) in an air oven with an ascending series of
temperatures (from room temperature to 90°C with a gradient of 10°C increment per stage),
e) sintering the mold at 700 to 750°C for 0.2 to 2 minutes to obtain bone grafting
scaffold;
f) cutting the scaffold as obtained in step (e) to required dimension and shape.
8. A process of making porous bone filler materials which comprises controlled grinding of porous bioceramic scaffolds and sieving to produce a coarse powder in the range of 0.5 to 1.5 mm grains for use as bone filler materials.
9. A process of making porous bioactive scaffolds, porous bone filler materials, nano sized calcium hydroxy apatite powder or a composite with other calcium phosphates substantially as herein described with reference to the examples.

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Patent Number

268374

Indian Patent Application Number

620/DEL/2009

PG Journal Number

35/2015

Publication Date

28-Aug-2015

Grant Date

27-Aug-2015

Date of Filing

27-Mar-2009

Name of Patentee

COUNCIL OF SCIENTIFIC & INDUSTRIAL RESEARCH

Applicant Address

ANUSANDHAN BHAWAN, RAFI MARG, NEW DELHI-110 001, INDIA

Inventors:

#	Inventor's Name	Inventor's Address
1	DATTA SOMESWAR	CENTRAL GLASS & CERAMIC RESEARCH INSTITUTE, 196 RAJA S.C.MULLICK ROAD, P.O.JADAVPUR UNIVERSITY, KOLKATA 700 032
2	BASU DEBABRATA	CENTRAL GLASS & CERAMIC RESEARCH INSTITUTE, 196 RAJA S.C.MULLICK ROAD, P.O.JADAVPUR UNIVERSITY, KOLKATA 700 032
3	GHOSH SAMIR KUMAR	CENTRAL GLASS & CERAMIC RESEARCH INSTITUTE, 196 RAJA S.C.MULLICK ROAD, P.O.JADAVPUR UNIVERSITY, KOLKATA 700 032

PCT International Classification Number

C07D

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA