FORM 2
THE PATENTS ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
"CO-PROCESSED SODIUM ALGINATE AS AN INACTIVE INGREDIENT
FOR DRUG DELIVERY"
2. APPLICANT (S):
(a) NAME: FDC Limited
(b)NATIONALITY: Indian Company incorporated under the Companies Act, 1956
(c) ADDRESS: 142-48, S.V. Road, Jogeshwari (West), Mumbai - 400 102, Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION:
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 a novel composition comprising co-processed sodium alginate, process for preparation and application of the co-processed sodium alginate, as an inactive ingredient in the pharmaceutical dosage forms.
BACKGROUND AND PRIOR ART:
Excipients are integral components of finished dosage forms other than active drug substances. Pharmaceutical excipients are incorporated into the formulations for their specific role and well defined functions, which improve the performance of dosage forms. Excipients differ from each other by their molecular weight, chemistry and physicochemical properties. Excipients have been obtained from synthesis, semi synthesis, processing of natural materials, bio-processing and fermentation technologies. Excipients, even though present in small quantity, may have their own role and hence impact the performance of dosage forms. Role of pharmaceutical excipients
• Improve the manufacturability
• Increase the pharmaceutical properties such as size, hardness, disintegration, low friability, viscosity, texture, appearance, color, flavor etc
• Retain the physicochemical properties such as particle size and polymorphism
• Enhance the chemical stability
• Enhance the drug solubility and permeability
• Enhance the bioavailability
• Reduce the dosing frequency and thus improves the patient compliance and the therapeutic efficacy
Pharmaceutical excipients are used to improve the organoleptic properties such as optimal size and acceptable taste, odor and color. The organoleptic properties of dosage forms are the key factors for patient compliance especially with pediatric and geriatric population. The stability of the formulation during storage also impacts the organoleptic properties and hence there is a need for stabilization of those organoleptic properties of the dosage form using suitable excipients. Viscosity modifiers are widely used in suspension dosage form to impart physical stability as well as better visual appearance during storage. In

many instances pharmaceutical excipients are incorporated in dosage forms, to improve pharmaco-technical properties such as disintegration, dissolution, hardness, friability etc. The quantity and quality of excipients in dosage forms determines the safety, efficacy, acceptability and cost of the therapy. Excipients such as lubricants and glidants improve the dosage form properties and provide better productivity for large scale manufacturing.
Excipients used in controlled release dosage forms are classified into two types such as release controlling substances and non-release controlling substances. The release controlling substances are used in the novel dosage forms such as modified release tablets, controlled release tablets, transdermal patches and parenteral depot preparations. These substances provider pre-programmed release of active ingredients from the dosage form and hence offer desired in vitro and in vivo release of drug(s). The pre-programmed release from dosage forms alters the pharmacokinetic profiles such as Cmax, Tmax, AUC and half life of the drug substances that could be effectively utilized to rationalize the drug therapy and offer better clinical outcomes.
Physical mixtures are simple admixtures of two or more excipients typically produced by short-duration low-shear processing. They may be either liquids or solids, and are generally used for convenience rather than for facilitating the manufacturing process or improving the resultant pharmaceutical product. However, such physical mixtures are not preferred for formulation because the individual components are isolated (distinct and intact) before mixing; i.e., the manufacturing process of each of the individual components is taken to completion, and consequently these components are adequately controlled before mixing.
Co-processed excipients are combinations of two or more excipients that possess performance advantages that cannot be achieved using a physical admixture of the same combination of excipients. They are produced using some form of specialized manufacturing process such as fluid bed processing, co grinding, spray drying, melt extrusion, extrusion, co milling co precipitation and other co granulation techniques.
The co-processed and modified excipients play very important role in the rapid development of dosage form that provides minimum batch to batch variability. Moreover,

co-processed excipients reduce the complexity of manufacturing process, time and solvents. Compared with existing excipients, the improved physical, mechanical, and chemical properties of such excipients have helped in solving formulation problems such as flowability, compressibility, hygroscopicity, palatability, dissolution, disintegration, sticking and dust generation.
US 4744987 discloses a particulate co-processed microcrystalline cellulose and calcium carbonate composition having the respective components present in a weight ratio of about 75:25 to 35:65, and which is useful as an excipient in pharmaceutical formulations.
EP 0998266 discloses pharmaceutical suspensions in which a pharmaceutically active ingredient is suspended with attrited microcrystalline cellulose co-processed and at least partially surface-coated with a calcium/ sodium alginate complex as a barrier dispersant.
J Pharm Pharmaceut Sci 8(1):76-93, 2005, has focused on the properties of the co-processed directly-compressible adjuvants available in the market.
AAPS PharmSciTech 2007; 8 (1) Article 9, E1-E7, discloses co-processed superdisintegrant consisting of crospovidone and SSG, exhibiting good flow and compression characteristics. Cefixime trihydrate and ibuprofen tablets containing co-processed superdisintegrant, exhibits quick disintegration and improved drug dissolution properties.
Sodium alginate consists of the sodium salt of alginic acid. It occurs as odourless, tasteless, white to yellowish brown filamentous, grainy, granular or powdered forms. It dissolves slowly in water, forming a viscous solution, insoluble in ethanol and ether. It is a linear copolymer with homopolymeric blocks of (l-4)-linked p-D-mannuronate (M) and its C-5 epimer α-L-guluronate (G) residues, covalently linked together in different sequences or blocks.
Although sodium alginate is a hygroscopic material, it is stable if stored at low relative humidity and cool temperature. Aqueous solutions are most stable at pH 4-10. Below pH 3, alginic acid precipitates. A 1% w/v aqueous solution of sodium alginate exposed to

differing temperatures, has a viscosity which is 60-80% of its original value after storage for 2 years.
Sodium alginate is widely used in cosmetics, food products and pharmaceutical formulations, such as tablet and capsule disintegrant, tablet binder, viscosity increasing agent, stabilizing agent and suspending agent for suspensions, and topical products including wound dressings. In tablet formulations, sodium alginate may be used both as a binder and disintegrant; it has been used as a diluent in capsule formulations. Sodium alginate has also been used in the preparation of sustained-release oral formulations, since it can delay the dissolution of a drug from tablets, capsules and aqueous suspensions. In topical formulations, sodium alginate is widely used as a thickening and suspending agent in a variety of pastes, creams and gels, and as a stabilizing agent for oil-in-water emulsions. Moreover, sodium alginate is widely used as an active ingredient in the treatment of Gastro Esophageal Reflux disorder. Sodium alginate is classified as a pH dependent polymer, and hence used to formulate the pH dependent matrix systems that can be used to design controlled release tablets, modified release tablets and gastroretentive dosage forms. Sodium alginate interacts with gastric acid in presence of calcium ion, and hence provides good gel strength due to calcium ion induced cross-linking. This gel strength results in high viscosity diffusion barrier, which retards the drug release. The viscosity of gel is based on the amount of sodium alginate, calcium ions, presence of other hydrogels in formulations, gastric pH and other physiological phenomenon such as buffering capacity and gastric motility. Gastroretentive dosage forms are designed to improve the rate and extent of drug absorption, as well as to provide the controlled release profile of drug molecules, which are least absorbed or unstable in latter part of gastrointestinal tract. Gastroretention can be achieved by combination of one or more mechanisms such as floating dosage form, high density dosage forms, bioadhesive dosage forms and expandable dosage form.
Floating drug delivery systems have been explored extensively to improve the safety as well as efficacy of drug substances. Floating dosage forms have low bulk density when compared with gastric fluid, and are thereby retained in the stomach for prolonged period of time, despite of gastric emptying. Floating dosage forms have many distinct advantages such as ease of manufacturing, robust formulation, ease of scale up,

established in vitro techniques, low cost and predictable pharmacokinetics. However, the excipients of choice are limited, and hence there is need to invent new excipients for floating drug delivery. Sodium alginate in combination with carbonate and bicarbonates, is widely used as an excipient of first choice in floating drug delivery system. Sodium alginate interacts with gastric acid in presence of calcium ion, at the same time sodium bicarbonate reacts with HCI and liberates CO2. The liberated C02 is entrapped in sodium alginate gel matrix and hence offers low density, which helps floating of the dosage form in gastric fluid.
However, sodium alginate based matrix system requires wet granulation process to achieve robust formulation, better uniformity and reproducible drug release. In non aqueous wet granulation, carbonates and bicarbonates remain insoluble during granulation and hence particle size distribution of carbonates and bicarbonates plays an important role in matrix integrity, gas generation and drug release. Aqueous granulation is considered as an optimal method of granulation for sodium alginate based matrix system. However, the process parameters such as drying, volume of granulating solvent, presence of other inactive ingredients along with nature of active pharmaceutical ingredients play a key role in crystallization and distribution of carbonates and bicarbonates in granules. The small variation in process parameters significantly influences the carbonates and bicarbonates distribution pattern and crystalline nature in granules, and hence affects the floating lag time, gel strength, drug release, bioavailability and therapeutic efficacy.
In order to achieve the robust, reproducible and scalable sodium alginate based matrix system, it is essential to maintain the uniformity and homogeneity along with uniform crystalline and/or amorphous state of carbonates and bicarbonates as well as sodium alginate. Thus, there is a need to develop sodium alginate, a versatile excipient with better pharmaceutical properties such as flow property, bulk density, hardness, viscosity and better consistency in drug release.
The present invention has accomplished the same by co-processing of sodium alginate together with carbonates and/or bicarbonates that offers numerous advantages in

pharmaceutical properties, drug release and in vivo performance, for which the protection is sought.
OBJECTS OF THE INVENTION:
The primary objective of the present invention is to design co-processed sodium alginate as an inactive ingredient which will be suitable for manufacturing various pharmaceutical dosage forms.
Another object of the present invention is to provide co-processed sodium alginate that provides superior pharmaceutical properties such as bulk density, particle size, content uniformity, viscosity and drug release texture.
Yet another object of the present invention is to provide co-processed sodium alginate, which will provide minimum batch to batch variability, cost effective manufacturing and time effective manufacturing.
The further object of the present invention to provide co-processed sodium alginate, which will give better consistency in in-vitro and in-vivo drug release of dosage forms.
SUMMARY OF THE INVENTION:
In accordance with the above objective, the present invention describes novel composition, process and application of co-processed sodium alginate, which will be used as an inactive ingredient in pharmaceutical dosage forms.
According to one aspect, the present invention provides co-processed sodium alginate with narrow particles size distribution, homogeneity, low crystalline nature and better pharmaceutical properties such as good flowability, non-stickiness and compressibility.
In another aspect, the co-processed sodium alginate may be effectively employed for formulation of tablet dosage forms using direct or non aqueous granulation. Sodium alginate based matrix tablets using co-processed sodium alginate provides robust,

reproducible and scalable formulation with minimum variability in in-vitro as well as in-vivo drug releases. Co-processed sodium alginate with carbonate or bicarbonate provide uniform distribution of sodium alginate and carbonate or bicarbonate, which in turn gives uniform swelling behavior , reproducible drug release and floating behavior with minimum process variation. Better control over the particle size of co-processed excipient will provide minimum batch to batch variability in drug release.
In another aspect, co-processed sodium alginate may be effectively used as an excipient in chewable tablets, immediate release tablets, dry suspensions, dry syrups and other liquid dosage forms.
In yet another aspect, the invention provides a process for preparation of co-processed sodium alginate together with carbonate or bicarbonate and optionally with other inactive excipients suitable for pharmaceutical manufacturing.
DETAILED DESCRIPTION OF THE INVENTION:
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.
Accordingly, the present invention describes the new composition, process and application of co-processed sodium alginate, which will be used as inactive ingredient in pharmaceutical dosage forms.
Co-processed sodium alginates of the present invention will be used as inactive ingredients in the dosage form such as oral solids, liquids and topicals to provide better pharmaceutical properties such as flow, bulk density, hardness, viscosity and drug release. Further, co-processed sodium alginates of the present invention will give better consistency in in-vitro and in-vivo drug release of dosage forms.
According to the present invention, drug release profile from the co-processed sodium alginate incorporated dosage form is based on the viscosity and composition (guluronic acid and mannuronic acid ratio) of the same, For example high guluronic acid induces

low viscosity and provides rapid release and is hence suitable for immediate release dosage forms, whereas high viscosity of sodium alginate in co-processed sodium alginate results in controlled release profile of the dosage form.
Thus the pharmaceutical formulations prepared using co-processed sodium alginate of the present invention would be an immediate release formulation, controlled release dosage forms, sustained release dosage forms, extended release dosage forms and gastroretentive dosage forms.
Co-processed sodium alginates of the present invention is used to formulate liquid dosage forms such as solutions, suspensions and gels, solid dosage forms such as tablets, granules, powders, mini tablets, capsules and pellets, and semi solid dosage forms such as creams, ointment and pastes.
Co-processed sodium alginates, preferably consists of sodium alginate and carbonate(s) and/or bicarbonate(s) along with optional ingredients.
Carbonates and bicarbonates are selected from the group of sodium bicarbonate, sodium carbonate, calcium carbonate, calcium bicarbonate, potassium carbonate, potassium bicarbonate, zinc carbonate and zinc bicarbonate and optionally other ingredients such as silicon dioxide, calcium salts, potassium salts, zinc salts and sodium salts.
The ratio of sodium alginate to carbonate and/or bicarbonate in the co-processed sodium alginate is 30:1 to 1:1.
In another embodiment, co-processed sodium alginate can be prepared by using one of the following techniques such as spray drying, tray drying, freeze drying, fluidized bed drying, co precipitation and co evaporation.
In a preferred embodiment the co-processed sodium alginate is prepared by dissolving and/or dispersing sodium alginate and bicarbonate(s) or carbonate(s) in suitable solvent or mixture of solvents. The other optional solid contents such as silicon dioxide, calcium salts, potassium salts, zinc salts and sodium salts can also be incorporated into the

dispersion or solution. The final suspension is dried to get the free flowing powder of desired particle size.
The particle size of the co-processed excipient ranges from 1 micron to 1000 micron.
Suitable solvent used for the purpose of dissolution or dispersion is selected from but not limited to water, ethanol, methanol, isopropanol, methylene dichloride, acetone and mixture thereof.
EXAMPLES:
Example 1:
Sodium alginate - ] 00 g
Sodium bicarbonate - 100 g
Water - qs
Sodium bicarbonate is dissolved in water to obtain a solution and sodium alginate is
dispersed in the said solution to get a clear colloidal solution. The said colloidal solution
is spray dried. The desired moisture content and particle size is controlled by process
optimization such as spray rate and inlet temperature.
Particle Size: 90% of the particle less than 200 micron
Inlet temperature: 160 °C
Example 2:
Sodium alginate - 300 g
Sodium bicarbonate- 10g
Water - qs
Sodium bicarbonate is dissolved in water and sodium alginate is dispersed in the same to
get a clear colloidal solution. The obtained colloidal solution is spray dried. The desired
moisture content and particle size is controlled by process optimization such as spray rate
and inlet temperature.
Particle Size: 90% of the particle less than 400 micron
Inlet temperature: 185 °C
Spray drying of sodium alginate along with carbonates offer porous uniform spherical particles. The porosity of the particles offer huge surface area for contact with the

biological fluids that provide faster drug release and onset of action. These spray dried alginates can be incorporated in the mouth dissolving or dispersing tablets to achieve better mouth feel and palatability
Example 3:
Sodium alginate - 100 g
Calcium carbonate - 40g
Water - qs
Calcium carbonate and sodium alginate is dispersed in water to get a smooth colloidal
dispersion. The obtained colloidal solution is spray dried. The desired moisture content
and particle size is controlled by process optimization such as spray rate and inlet
temperature
Example 4:
Sodium alginate - 100 g
Calcium carbonate - 40g
Colloidal silicon dioxide - 2.8 g
Water - qs
Calcium carbonate and colloidal silicon dioxide are dispersed in water and sodium
alginate is dispersed to get a smooth colloidal dispersion. The obtained solution is spray
dried. The desired moisture content and particle size is controlled by process optimization
such as spray rate and inlet temperature
Example 5:
Sodium alginate - 100 g
Sodium bicarbonate - 40g
Colloidal silicon dioxide - 2.8 g
Calcium hydroxide - 0.25 g
Water - qs
Sodium bicarbonate, calcium hydroxide and colloidal silicon dioxide are dissolved and/or
dispersed in water and sodium alginate is dispersed to get a smooth colloidal dispersion.
The obtained solution is spray dried. The desired moisture content and particle size is
controlled by process optimization such as spray rate and inlet temperature.

WE CLAIM;
1. A pharmaceutical excipient composition comprising co-processed sodium alginate along with carbonate(s) and/or bicarbonate(s) and optionally with other inactive ingredients.
2. The pharmaceutical excipient composition as claimed in claim 1, wherein the carbonates are selected from a group consisting of sodium carbonate, calcium carbonate, potassium carbonate and zinc carbonate.
3. The pharmaceutical excipient composition as claimed in claim I, wherein the bicarbonates are selected from a group consisting of sodium bicarbonate, calcium bicarbonate, potassium bicarbonate and zinc bicarbonate.
4. The pharmaceutical excipient composition as claimed in claim 1, wherein the other inactive ingredients are selected from a group consisting of silicon dioxide, calcium salts, potassium salts, zinc salts and sodium salts.
5. The pharmaceutical excipient composition as claimed in claim 1, wherein the ratio of sodium alginate to carbonate and/or bicarbonate in the co-processed sodium alginate is 30:1 to 1:1.
6. The pharmaceutical excipient composition as claimed in claim 1, wherein said composition is used for formulating liquid dosage forms such as solutions, syrups, suspensions and gels; solid dosage forms such as tablets, granules, powders, mini tablets, capsules and pellets; and semi-solid dosage forms such as creams, ointments and pastes.
7. The pharmaceutical excipient composition as claimed in claim 6, wherein said composition is used for formulating immediate release dosage forms, controlled release dosage forms, sustained release dosage forms, extended release dosage forms and gastroretentive dosage forms.

8. A process for manufacturing a pharmaceutical excipient composition as claimed in claim 1, comprising co-processing sodium alginate together with carbonates and/or bicarbonates and other inactive ingredients, by dissolving and/or dispersing sodium alginate and carbonate(s) and/or bicarbonate(s) in suitable solvent(s) to get a colloidal solution/dispersion, optionally incorporating other inactive ingredients into the colloidal solution/dispersion; and drying the colloidal solution/suspension to get free flowing powder of co-processed sodium alginate having particle size of 1 to 1000 microns.
9. The process for manufacturing the pharmaceutical excipient formulation as claimed in claim 8, wherein the suitable solvent is selected from a group consisting of water, ethanol, methanol, isopropanol, methylene dichloride and acetone.