Title of Invention	"PREPARATION AND USE OF OLIGOSACCHARIDE IMPRINTED MESOPOROUS SILICA"
Abstract	The present invention relates to preparation and use of silica materials using oligosaccharide as a template under mild acidic or basic conditions. The reaction for the preparation of silica takes place at ambient condition in presence of acid or a base. The obtained silica shows potential applications in modification of physical properties such as conversion from liquid to solid state of the material, aqueous solubility enhancement. adsorption and flow promotion.

Title of Invention

"PREPARATION AND USE OF OLIGOSACCHARIDE IMPRINTED MESOPOROUS SILICA"

Abstract

The present invention relates to preparation and use of silica materials using oligosaccharide as a template under mild acidic or basic conditions. The reaction for the preparation of silica takes place at ambient condition in presence of acid or a base. The obtained silica shows potential applications in modification of physical properties such as conversion from liquid to solid state of the material, aqueous solubility enhancement. adsorption and flow promotion.

Full Text	FORM 2 THE PATENTS ACT, 1970 (39 OF 1970) & THE PATENTS RULES, 2003 COMPLETE SPECIFICATION (Section 10 and rule 13) 1. "PREPARATION AND USE OF OLIGOSACCHARIDE IMPRINTED MESOPOROUS SILICA" 2. (a) Amin Purnima Dhanraj (b) Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Nathalal Parekh Marg., Matunga. Mumbai 400019, Maharashtra, India. (c) INDIAN. The following specification particularly describes the invention and the manner in which it is to be performed. FIELD OF INVENTION: The present invention relates to an improved process for preparation of template, under agitation in acidic or basic condition. This is a novel high yielding process for preparing such mesoporous silica. The reaction takes place at ambient condition and requires shorter times. The cavitational effects generated due to templates plays an important role of enhancing the surface area of the material and generating the mesopores within. BACKGROUND OF INVENTION: Preparation of mesoporous silica is one of the most widely studied reaction. The realm of mesoporous materials was extended after the emergence of Kresge's method for the preparation of mesoporous silica materials (MCM-41) through the use of surfactants as organizing agents; however, the present invention is devoid of using any surfactant during the hydrolysis. Several generalized procedures implementing various self assembling strategies for the hydrolysis of silica in a well defined (ordered) environment are known in the literature for the synthesis of mesoporous silica which are as follows: The use of ionic liquids in the synthesis of mesoporous materials is well established, as reported by Xiaodi Liu et. al. "Applications of ionic liquid in the convenient synthesis of nanomaterials", Review on advanced material sciences, 27 (2011) 43-51 and Jianmei Pang et. al. "Ionic-liquid assisted synthesis of silica particles and their application in drug release", Material letters, 2010 doi: 10.1016/j.matlet.2010.08.032. Another example implementing hydrolysis of silica precursor in self assembled system is of using a surfactant as reported by Shunai Che et. al. "A novel anionic surfactant templating route for synthesizing mesoporous silica with unique structure", Nature materials, 2 (2003) 801-805 and Valeria Ambrogi et. al. "Role of mesoporous silicates on carbamazepine dissolution rate enhancement', Microporous and mesoporous materials. 113(2008)445-452. Silica precursor hydrolysis using an ordered block copolypeptides templating system was reported by Jennifer Cha et. al. "Biomimetic synthesis of ordered silica structures mediated by block copolypeptides", Nature, 403 (2000) 289-292. Postsynthesized tailored mesoporous silica was used as a solubility enhancing agent by Yanzhuo et.al. The material needs to be processed postsynthesized incorporating additional cost and tediousness to the process "Spherical mesoporous silica nanoparticles for loading and release of the poorly water soluble drug telmisartan", Journal of controlled release, 145(2010) 257-263. SBA15, typical mesoporous silica was also explored without removing the structure directing template surfactant from the material for dissolution improvement in drug delivery applications by Fu Tingming et, al. "Template occluded SBA15: an effective dissolution enhancer for poorly water soluble drug", Applied surface sciences, 256(2010)6963-6968. It is an objective of this invention to provide a simple and cost effective process for preparing mesoporous silica using a non surfactant based system at a shorter reaction time. A further objective of the invention is to provide the potential use of the material in adsorption, entrapment and solubility enhancement of various materials. SUMMARY OF THE INVENTION: One aspect of the present invention relates to synthesis of mesoporous silica from a silica precursor using some structure directing agent (template occlusion) in presence of acid or base. Another aspect of the present invention is to explore the developed material as a carrier, adsorbent, entrapping agent. Yet another objective of the present invention is to provide a process for solubility enhancement of poorly water soluble materials, which includes but not limited to, Itraconazole, Bicalutamide, Valsartan, Carvedilol, Artemether, Curcumine, and Carbamazepine etc. The present invention provides a process for the use and preparation of mesoporous silica compounds using cyclodextrin as a structure directing agent in presence of hydrochloric acid. The subject method provides improvement in many features and is as follows: The present invention provides rapid preparation of mesoporous silica i.e. the present invention shows a significant enhancement in the reaction rate in presence of acidic solution of cyclodextrin under agitation as compared to similar reaction performed under silent conditions. The developed material was used in wide range of compounds having different steric and electronic properties providing good yields of the desired products. According to present invention, it becomes possible to carry out synthesis of mesoporous materials and drug loading on the same, at a low cost without necessity to invest a large sum of money in plant and equipments. DETAIL DESCRIPTION OF THE INVENTION: One aspect of the present invention relates to mesoporous silica preparation from a precursors in presence of a structure directing agent. Second aspect of the present invention is use of the material as solubility enhancer, carrier, adsorbent etc. for the compounds like bicalutamide, valsartan, carvedilol and valproic acid etc. under milder operating conditions. The liquid silica precursor compounds useful in the practice of the present invention are those having molecular formula Si-(OR)4, wherein R is individually alkyl substituents, which may be same or different. Typical of such radicals are alky groups such as methyl, ethyl, propyl, isopropyl, and the like. The reaction uses structure directing agents from the family of polysaccharides and oligosacchardies more preferably from the family of cyclodextrin which include but not limited to α-cyclodextrin, β-cyclodextrin, γ- cyclodextrin and most preferably form β-cyclodextrin and its derivatives. The quantity ratio between the silica precursor and the structure directing template varies from 1:1 to 1:5. Obviously the amount of cyclodextrin employed need only be sufficient to produce the pores onto the silica surface. The reaction can be conducted over a wide range of temperatures and pressure. For convenience the reaction is conducted at atmospheric pressure. The reaction temperature is not lower than the melting point of the substrates and not higher than the boiling point thereof. During the reaction a sol to gel transition takes place within an hour. Further the solid is calcined at 600 C for template removal. The material is unique and can be used as a solubility enhancer, carrier and adsorbent. A compound can be loaded on mesoporous silica by simple mixing, kneading. trituration, slurry, ball milling, spray drying, solvent evaporation or extrusion process. The process and use of the present invention is further described with reference to the following examples which are illustrative only and should not be construed to limit the scope of the present invention. EXAMPLE 1 In a typical reaction, Hdroxy propyl beta cyclodextrin (4g) was dissolved in Conc. H2SO4 solution of pH 2 then Tetraethyl orthosilane (8g) was added and the sol was agitated at room temperature (25°C) in a clean round bottom flask. The reaction was carried out in a 100 ml capacity round bottom flask with a magnetic agitator. Over the period of an hour sol to gel transformation takes place. The system left overnight as it is. The pale yellowish solid so formed is then subjected to calcinations for purification and template removal at 600 °C for six hours. Yield was found to be 90%. EXAMPLE 2 The charge similar to that of given in example 1 was taken except that hydrochloric acid was used instead of H2SO4. The reaction was completed in 2 hours. Yield of the reaction was found to be 80%. EXAMPLE 3 Tetraethyl orthosilane (2.5g), cyclohexane (30mL), ethanol (1.5 mL) was mixed. Another solution was prepared by mixing water (30mL), urea (0.6g). This solution was added to the previous under vigorous agitation. Sol to gel transformation takes place over the period of 3 to 8 hours. The material is then further dried at 60 °C overnight followed by 600°C calcinatin. EXAMPLE 4 The material formed in example 1 was suspended in acetone. Bicalutamide was added in the solution (ratio of silica to bicalutamide is 2:1) the system was subjected to magnetic stirring till the acetone evaporated completely. When solubility kinetics of bicalutamide loaded on mesoporous silica was performed it has been observed a 1,66 times increased as compared to that of plain bicalutamide. This is very useful in bioavailability improvement of the drugs belonging to BCS class II. EXAMPLE 5 Mesoporous silica given in example 1 was suspended in acetone. Bicalutamide was added to blend (ratio of bicalutamide to silica 3:17) polyethylene glycol 400 was also added in same quantity as of bicalutamide. Mixing of the system was continued till complete evaporation of acetone. The dried material is collected and subjected to solubility studies. Bicalutamide loaded on mesoporous silica showed a significant enhanced solubility of 4 times as compared to plain bicalutamide. EXAMPLE 6 The mesoporous material of example 1 was explored as a carrier for the conversion of liquid material to solid. Valproic acid a liquid drug was mixed with mesoporous silica in a ratio of 1:2 in mortar and pestle for 30 min. The white free flowable solid was obtained indicating complete adsorption of drug onto the solid support. Thus this reduced the liquid handling costs and precautions. We Claim: 1. An improved process for preparation of mesoporous silica using oligosaccharide as a template in presence of acid or base, and use of this material as adsorbent. solubility enhancer and carrier. 2. A process as claimed in claim 1 wherein the templating agent is cyclodextrin. 3. A process as claimed in claiml wherein the starting material used as a silica precursor belongs to silicon alkoxide or metal silicate family. 4. Use of the material resulted from claim 1 as adsorbent, solubility enhancer, carrier and flow promoter. 5. A process as claimed in claiml for hydrolysis of the silica precursor in the temperature range of 20-80 °C with stirring.

Full Text

FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
(Section 10 and rule 13)
1. "PREPARATION AND USE OF OLIGOSACCHARIDE IMPRINTED MESOPOROUS
SILICA"
2. (a) Amin Purnima Dhanraj
(b) Department of Pharmaceutical Sciences and Technology,
Institute of Chemical Technology,
Nathalal Parekh Marg., Matunga. Mumbai 400019, Maharashtra, India.
(c) INDIAN.
The following specification particularly describes the invention and the manner in which it is to be performed.

FIELD OF INVENTION:
The present invention relates to an improved process for preparation of
template, under agitation in acidic or basic condition. This is a novel high yielding process for preparing such mesoporous silica. The reaction takes place at ambient condition and requires shorter times. The cavitational effects generated due to templates plays an important role of enhancing the surface area of the material and generating the mesopores within.
BACKGROUND OF INVENTION:
Preparation of mesoporous silica is one of the most widely studied reaction. The realm of mesoporous materials was extended after the emergence of Kresge's method for the preparation of mesoporous silica materials (MCM-41) through the use of surfactants as organizing agents; however, the present invention is devoid of using any surfactant during the hydrolysis. Several generalized procedures implementing various self assembling strategies for the hydrolysis of silica in a well defined (ordered) environment are known in the literature for the synthesis of mesoporous silica which are as follows:
The use of ionic liquids in the synthesis of mesoporous materials is well established, as reported by Xiaodi Liu et. al. "Applications of ionic liquid in the convenient synthesis of nanomaterials", Review on advanced material sciences, 27

(2011) 43-51 and Jianmei Pang et. al. "Ionic-liquid assisted synthesis of silica particles
and their application in drug release", Material letters, 2010 doi:
10.1016/j.matlet.2010.08.032.
Another example implementing hydrolysis of silica precursor in self assembled system is
of using a surfactant as reported by Shunai Che et. al. "A novel anionic surfactant
templating route for synthesizing mesoporous silica with unique structure", Nature
materials, 2 (2003) 801-805 and Valeria Ambrogi et. al. "Role of mesoporous silicates on
carbamazepine dissolution rate enhancement', Microporous and mesoporous materials.
113(2008)445-452.
Silica precursor hydrolysis using an ordered block copolypeptides templating system was
reported by Jennifer Cha et. al. "Biomimetic synthesis of ordered silica structures
mediated by block copolypeptides", Nature, 403 (2000) 289-292.
Postsynthesized tailored mesoporous silica was used as a solubility enhancing agent by Yanzhuo et.al. The material needs to be processed postsynthesized incorporating additional cost and tediousness to the process "Spherical mesoporous silica nanoparticles for loading and release of the poorly water soluble drug telmisartan", Journal of controlled release, 145(2010) 257-263.
SBA15, typical mesoporous silica was also explored without removing the structure directing template surfactant from the material for dissolution improvement in drug delivery applications by Fu Tingming et, al. "Template occluded SBA15: an effective dissolution enhancer for poorly water soluble drug", Applied surface sciences, 256(2010)6963-6968.
It is an objective of this invention to provide a simple and cost effective process for preparing mesoporous silica using a non surfactant based system at a shorter reaction time. A further objective of the invention is to provide the potential use of the material in adsorption, entrapment and solubility enhancement of various materials.
SUMMARY OF THE INVENTION:
One aspect of the present invention relates to synthesis of mesoporous silica from a silica precursor using some structure directing agent (template occlusion) in presence of acid or base. Another aspect of the present invention is to explore the developed material as

a carrier, adsorbent, entrapping agent. Yet another objective of the present invention is to provide a process for solubility enhancement of poorly water soluble materials, which includes but not limited to, Itraconazole, Bicalutamide, Valsartan, Carvedilol, Artemether, Curcumine, and Carbamazepine etc.
The present invention provides a process for the use and preparation of mesoporous silica compounds using cyclodextrin as a structure directing agent in presence of hydrochloric acid. The subject method provides improvement in many features and is as follows:
The present invention provides rapid preparation of mesoporous silica i.e. the present invention shows a significant enhancement in the reaction rate in presence of acidic solution of cyclodextrin under agitation as compared to similar reaction performed under silent conditions.
The developed material was used in wide range of compounds having different steric and electronic properties providing good yields of the desired products.
According to present invention, it becomes possible to carry out synthesis of mesoporous materials and drug loading on the same, at a low cost without necessity to invest a large sum of money in plant and equipments.
DETAIL DESCRIPTION OF THE INVENTION:
One aspect of the present invention relates to mesoporous silica preparation from a precursors in presence of a structure directing agent. Second aspect of the present invention is use of the material as solubility enhancer, carrier, adsorbent etc. for the compounds like bicalutamide, valsartan, carvedilol and valproic acid etc. under milder operating conditions. The liquid silica precursor compounds useful in the practice of the present invention are those having molecular formula Si-(OR)4, wherein R is individually alkyl substituents, which may be same or different. Typical of such radicals are alky groups such as methyl, ethyl, propyl, isopropyl, and the like. The reaction uses structure directing agents from the family of polysaccharides and oligosacchardies more preferably from the family of cyclodextrin which include but not limited to α-cyclodextrin, β-cyclodextrin, γ- cyclodextrin and most preferably form β-cyclodextrin and its derivatives.

The quantity ratio between the silica precursor and the structure directing template varies from 1:1 to 1:5. Obviously the amount of cyclodextrin employed need only be sufficient to produce the pores onto the silica surface.
The reaction can be conducted over a wide range of temperatures and pressure. For convenience the reaction is conducted at atmospheric pressure. The reaction temperature is not lower than the melting point of the substrates and not higher than the boiling point thereof. During the reaction a sol to gel transition takes place within an hour. Further the solid is calcined at 600 C for template removal.
The material is unique and can be used as a solubility enhancer, carrier and adsorbent. A compound can be loaded on mesoporous silica by simple mixing, kneading. trituration, slurry, ball milling, spray drying, solvent evaporation or extrusion process. The process and use of the present invention is further described with reference to the following examples which are illustrative only and should not be construed to limit the scope of the present invention.
EXAMPLE 1
In a typical reaction, Hdroxy propyl beta cyclodextrin (4g) was dissolved in Conc. H2SO4 solution of pH 2 then Tetraethyl orthosilane (8g) was added and the sol was agitated at room temperature (25°C) in a clean round bottom flask. The reaction was carried out in a 100 ml capacity round bottom flask with a magnetic agitator. Over the period of an hour sol to gel transformation takes place. The system left overnight as it is. The pale yellowish solid so formed is then subjected to calcinations for purification and template removal at 600 °C for six hours. Yield was found to be 90%.
EXAMPLE 2
The charge similar to that of given in example 1 was taken except that hydrochloric acid was used instead of H2SO4. The reaction was completed in 2 hours. Yield of the reaction was found to be 80%.
EXAMPLE 3

Tetraethyl orthosilane (2.5g), cyclohexane (30mL), ethanol (1.5 mL) was mixed. Another solution was prepared by mixing water (30mL), urea (0.6g). This solution was added to the previous under vigorous agitation. Sol to gel transformation takes place over the period of 3 to 8 hours. The material is then further dried at 60 °C overnight followed by 600°C calcinatin.
EXAMPLE 4
The material formed in example 1 was suspended in acetone. Bicalutamide was added in the solution (ratio of silica to bicalutamide is 2:1) the system was subjected to magnetic stirring till the acetone evaporated completely. When solubility kinetics of bicalutamide loaded on mesoporous silica was performed it has been observed a 1,66 times increased as compared to that of plain bicalutamide. This is very useful in bioavailability improvement of the drugs belonging to BCS class II.
EXAMPLE 5
Mesoporous silica given in example 1 was suspended in acetone. Bicalutamide was added to blend (ratio of bicalutamide to silica 3:17) polyethylene glycol 400 was also added in same quantity as of bicalutamide. Mixing of the system was continued till complete evaporation of acetone. The dried material is collected and subjected to solubility studies. Bicalutamide loaded on mesoporous silica showed a significant enhanced solubility of 4 times as compared to plain bicalutamide.
EXAMPLE 6
The mesoporous material of example 1 was explored as a carrier for the conversion of liquid material to solid. Valproic acid a liquid drug was mixed with mesoporous silica in a ratio of 1:2 in mortar and pestle for 30 min. The white free flowable solid was obtained indicating complete adsorption of drug onto the solid support. Thus this reduced the liquid handling costs and precautions.

We Claim:
1. An improved process for preparation of mesoporous silica using oligosaccharide as a template in presence of acid or base, and use of this material as adsorbent. solubility enhancer and carrier.
2. A process as claimed in claim 1 wherein the templating agent is cyclodextrin.
3. A process as claimed in claiml wherein the starting material used as a silica precursor belongs to silicon alkoxide or metal silicate family.
4. Use of the material resulted from claim 1 as adsorbent, solubility enhancer, carrier and flow promoter.
5. A process as claimed in claiml for hydrolysis of the silica precursor in the temperature range of 20-80 °C with stirring.

Documents:

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Patent Number

279192

Indian Patent Application Number

2056/MUM/2011

PG Journal Number

03/2017

Publication Date

20-Jan-2017

Grant Date

13-Jan-2017

Date of Filing

19-Jul-2011

Name of Patentee

PURNIMA D. AMIN

Applicant Address

DEPARTMENT OF PHARMACEUTICAL SCIENCES AND TECHNOLOGY, INSTITUTE OF CHEMICAL TECHNOLOGY, NATHALAL PAREKH MARG, MATUNGA (EAST), MUMBAI-400 019 MAHARASHTRA, INDIA

Inventors:

#	Inventor's Name	Inventor's Address
1	MEER TARIQUE ALI SADIQUE ALI	DEPARTMENT OF PHARMACEUTICAL SCIENCES AND TECHNOLOGY, INSTITUTE OF CHEMICAL TECHNOLOGY, NATHALAL PAREKH MARG, MATUNGA (EAST), MUMBAI-400 019 MAHARASHTRA, INDIA
2	PATOLE RAHUL KASHINATH	DEPARTMENT OF PHARMACEUTICAL SCIENCES AND TECHNOLOGY, INSTITUTE OF CHEMICAL TECHNOLOGY, NATHALAL PAREKH MARG, MATUNGA (EAST), MUMBAI-400 019 MAHARASHTRA, INDIA
3	FULE RITESH AMOL	DEPARTMENT OF PHARMACEUTICAL SCIENCES AND TECHNOLOGY, INSTITUTE OF CHEMICAL TECHNOLOGY, NATHALAL PAREKH MARG, MATUNGA (EAST), MUMBAI-400 019 MAHARASHTRA, INDIA
4	AMIN PURNIMA DHANRAJ	DEPARTMENT OF PHARMACEUTICAL SCIENCES AND TECHNOLOGY, INSTITUTE OF CHEMICAL TECHNOLOGY, NATHALAL PAREKH MARG, MATUNGA (EAST), MUMBAI-400 019, MAHARASHTRA, INDIA

PCT International Classification Number

C23C14/00

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA