FORM-2
THE PATENTS ACT, 1970
COMPLETE
SPECIFICATION
SECTION 10
TITLE : PROCESS FOR THE PREPARATION OF NOVEL PHARMACEUTICAL COMPOSITION
APPLICANT (S): BLUE CROSS LABORATORIES LTD., A-12 AMBAD
INDUSTRIAL AREA, NASHIK 422 010, MAHARASHTRA, INDIA. AN INDIAN COMPANY.
The lollowing Specification particularly describes and ascertains the nature of this invention and the manner in which it is to be performed: -

FIELD OF INVENTION
The present invention re lates to a novel disintegrant for pharmaceutical preparations and in particular a novel disintegrant comprising Lepidium sativum husk powder as a novel natural superdisintegrating agent for pharmaceutical formulations along with viscosity building ability, an important features for dispersible tablets.
In pharmaceutical industry, oral solid unit dosage forms are the most advantageous dosage form for the administration of a therapeutically active agent or drug. For a pharmacist, solid unit dosage form is the most reliable and convenient dosage form to dispense because of its salient features like accurate dosing, easy dispensing and handling.
Additionally solid unit dosage forms are frequently employed for different purposes in industries other than pharmaceutical, like bleaching agents, detergent, perfumed bath water softeners, artificial sweeteners, weed-killers and dyes.
Oral solid unit dosage form contains number of inert materials in addition to active medicament. They are generally called as additives. They may be classified according to the role they play in the finished tablets. The first group contains those materials, which help to impart satisfactory compression characteristics to the formulation. These include diluents, Binders and lubricants. The second group of added substances helps to impart additional desirable physical properties to the finished product, included in this group are disintegrant(s), colours and in case of chewable and dispersible tablets flavours and sweetening agents. [Leon Lachman, HA. Lieberman, Joseph L. Kanig "The Theory and Practice of Industrial Pharmacy", Third edition, PP 325 - 329 (1987), Remington's Pharmaceutical Sciences, 17* edition, published by Mack publishing company, Pennsylvania, PP 1605 (1985)]
A disintegrant is a substance, which is when added to a oral solid unit dosage form, facilitate its breakup into fine particles after ingestion. This process helps the release of biologically absorbable drugs from the matrix allowing its rapid dissolution. Materials,
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used as disintegrants have been chemically classified as starches, clays, cellulose, alginates, gums, resins, polymers and crosslinked polymers.
The disintegrants are added directly to the dry ingredients, when the direct compression tabletting method is used. When the dry or wet granulation tabletting methods are used, the disintegrant may be added before granulation (intragranularly) or after granulation (extragranularly) or partly may be added intragranularly and partly added extragranularly.
It is well known fact to those who are skilled in the art that there are various material currently used in pharmaceutical industry, for the purpose of disintegration. These materials are microcrystalline cellulose and starch. Microcrystalline cellulose is used by pharmaceutical industry to serve different purposes viz diluent, binder and disintegrant. By virtue of its nature microciystalline cellulose adsorbs some of active pharmaceutical ingredients like Piroxicam, Rofecoxib, etc whereby it reduces their dissolution and in turn rate of absorption. Starch, traditionally used similar to microcrystaline cellulose to serve various purpose, but its major use is limited to its diluent and binder properties It is termed as poor disintegrant. fLeon Lachman, HA Lieberman, Joseph L. Kanig "The Theory and Practice of Industrial Pharmacy", Third edition, PP 328 (1987), Remington's Pharmaceutical Sciences, 17* edition, published by Mack publishing company, Pennsylvania, PP 1606- 1607(1985)]
Many attempts have been made to modify the cold water - swelling, characteristics of starches to improve their disintegration properties. These have included chemical and physical modifications of starch. Chemical derivatization has produced cold-water swelling, cold-water-soluble intact granular starches, such as starch phosphate, starch sulphate and carboxymethyl starch. US patent no. 3,034,911 issued on May 15, 1962 to IK. McKee et. al claims physical modification by compaction, with or without the use of supplemental thermal energy. The product produced partial cold-water-swelling, which is acting as binder / disintegrant.
To overcome the above imitations, the superdisintegrants like crospovidone, croscarmelose sodium were developed. These are essentially cross-linked products of natural or synthetic origin. Although they possess good disintegration properties, sometimes they have limitations in terms of use e.g. to make tablet dosage form for the
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patients on low sodium diet, use of croscarmelose sodium could be limited. Cross-linked polyvinylpyrrolidone (crospovidone) is one of the best super-disintegrant available to pharmaceutical industry, but because of the synthetic nature and critical manufacturing process conditions makes it very costly. In fact all the above disintegrants are relatively less economical, probably due to cross-linking step involved in their manufacturing.
U.S. Patent Nos. 5,886,166 ; 5,725,883 ; and 5,585,115, inter alia mentions Prosolv SMCC™ which is a silicified microcrystalline cellulose. Silicification of the microcrystalline cellulose is achieved by a patented process, resulting in an intimate association between the colloidal silica and microcrystalline cellulose. This product is available in a median particle size (by sieve analysis) in the region of 50 mm and 90 mn.
It is apparent from the prior art that all the excipients, which are presently used as superdisintegrants in pharmaceutical industry like Crospovidone, Croscarmelose sodium, Carboxymethyl starch and Low substituted Hydroxypropyl cellulose and many others., are principally modified and / or cross-linked starch derivatives, and being synthetic product have limitations in use and/or involve critical manufacturing process and are thus cost-extensive to obtain.
OBJECTS OF THE INVENTION
It is thus the basic object of the present invention to provide a suitable disintegrant which would be of natural origin and not involve the above modifications and/or complexity in manufacture of synthetic disintegrants presently in use.
Another object is to provide a superdisintegrant which would be safe and can be made easily available as a cost-effective disintegrant.
Another object of present invention is to provide a novel disintegrant as well as viscosity building agent for use in tablet, capsule or pellet dosage forms.
Further objective of the present invention is to provide a novel disintegrating agent which can be used with wide variety of pharmaceutical compositions containing different kind of
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pharmaceutical therapeutic agent namely acidic, basic or neutral having different solubilities ranging from highly soluble to practically insoluble molecules.
Yet another objective of the present invention is to provide a novel disintegrating agent having comparable disintegrating properties as that of various super disintegrants hitherto described in prior art and currently used by the pharmaceutical industry
Yet further object of the present invention is directed to provide a pharmaceutical composition incorporating novel disintegrant which would have comparable disintegrating properties as that of presently available superdisintegrants but would be cost-effective and avoid problems of synthetic disintegrants.
SUMMARY OF INVENTION
Thus according to one aspect of the present invention there is provided a disintegrant for pharmaceutical formulations comprising Lepidium sativum husk powder having a particle size in the range of l00m to 250m.
This Lepidium sativum powder can be obtained of cress seed husk which is obtained from seeds of Garden Cress Plant {Lepidium sativum, Family : Cruciferae) cultivated as a salad plant throughout India. Garden Cress is a small, herbaceous, glabrous, annual growing plant up to 50 cm. From ancient times, Garden Cress seeds, leaves, roots and flowers are regularly used for treating various diseases or disorders. Seeds are mainly used as laxative, aperients, diuretic, alternative tonic, demulcent, aphrodisiac and carminative. Mucilage of seeds allays the irritation of mucous coat of intestine.
Analysis of Cress seed revealed following compositions. Moisture 5.69 %, protein 23.5 %, fats 15.91 %, ash 5.7 %, phosphorous (P203) 1.65 %, Calcium 0.31 % and sulfur 0.9 %. The seeds contain an alkaloid (0.19 %) Glucotropoelin sinActive Pharmaceutical Ingredientsn (Choline ester of sinActive Pharmaceutical Ingredientsc acid), SinActive Pharmaceutical Ingredientsc acid, Mucilaginous matter (5 %) and uric acid (0.103 %). The mucilage consists of a mixture of cellulose (18.3 %) and uronic acid containing polysaccharides, acid hydrolysis of mucilage yields L-arabinose, D-galactose, L-rhamnose, D-galactouronic acid and D-glucose.
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The seed of garden cress is old household remedy for various disorders or diseases. Seeds are recommended for the dispersion of certain chronic enlargment of spleen. Emulsion made by soaking or boiling the seeds in eight times the weight of water , is given as a drink to relieve hiccups. (Bhavprakash, a ancient standaed book on Ayurveda) a powder of seed with sugar is fien remedy for indigestion, diarrhoea and dysentery. Seeds in combination with Coconut, ghee, sugar is very nutritious and is given to pregnant women and lactating mothers in the form of Laddoos. Thus there are quite a few references in ancient standard Indian medicinal books regarding safe consumption of seed of Lepidium sativum.
Adam et al performed a toxicity study of Lepidium sativum seeds using Wistar albino rats at 2 % (w/w) was found to be non-toxic, 10 % (w/w) was toxic but not fatal and 50 % (w/w) of the diet for 6 weeks was lethal and caused depression in growth rate and entero-hepato-nephrotoxicity. ("Effect of various levels of dietary Lepidium sativum in rats", Am. Jr. of Chinese Medi., 27 (3.4), p-397-405, 1999)
Patole et al studied the antidiabetic activity of Lepidium sativum seeds on 11 NIDDM subjects as well as 14 normal healthy subjects by administering 15 gm. seeds per day. In the long term (21 days) treatment they found that seeds possess some hypoglycemic activity. ("Effect of mucilaginous seeds on in vitro rate of starch hydrolysis and blood glucose levels of NIDDM, subjects with special reference to Garden Cress Seeds", Jr. of Medi. and Aromatic Plant Sci., 20 (4), p-1005-1008, December, 1998).
While such other conventional uses of Lepidium sativum such have been known, over the years none of the above known art teaches or hints at any possible use of Lepidium sativum seed husk. It is only by way of this invention that it is surprisingly found that inspite of two contradictory characteristics of the component {Lepidium sativum husk powder) that is the disintegrating property and the viscosity building ability it can serve as an effective disintegrant for the pharmaceutical formulations, especially in case of dispersible tablets formulated mainly for pediatric and geriatric patients. Being a product of natural origin it is not only safe but is also cost-effective.
The disintegration properties of Lepidium sativum husk powder, is found to be based upon its swelling characteristic. It is found that the mechanism for the disintegration of tablet
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into granules is based on 'bursting effect'. When the tablet containing Lepidium sativum husk powder as disintegrant comes into contact with water, the Lepidium sativum husk powder swells quickly and by virtue it exerts pressure on the compressed structure of the tablet, which results into disintegration.
Surprisingly enough it was found that the Lepidium sativum husk powder swells enough to bring about a significant increase in the volume of dosage form without blocking the porous structure of the dosage form. The concurrent increase in the volume and continued capillary action exerts a tremendous force within the dosage form and effect rapid disintegration of dosage form. The Lepidium sativum husk powder also possess gelling property by virtue of which, it imparts viscosity to the solution, which is very important characteristic in regards to dispersible tablets, where one requires homogeneity in the dispersed dosage form.
Importantly, it is identified that the particle size of husk powder plays a crucial role in controlling the efficacy of the material as super-disintegrant. For use as disintegrant Lepidium sativum husk powder should preferably have particle size in the range of 100 u to 250u, more preferably 100 to-200u.
Also, moisture content of the husk is found to play a significant role in accelerating the disintegration efficiency, e.g., a moisture content in the range of 1.5 to 2.5% is preferred.
The process as detailed in our copending application No. 560/MUM/2001 can be followed to obtain the Lepidium sativum seed husk with the above selective particle size and moisture content for use as disintegrant. Such a process basically involves the steps of (i) crushing the seeds to average particle size of between 250-350 urn, (ii) subjecting crushed mass to solvent extraction to remove lipophilic constituents of Lepidium sativum husk.
In accordance with another aspect of the present invention there is provided pharmaceutical composition comprise a pharmaceutical composition in solid dosage form comprising atleast one pharmaceutical therapeutic agent and Lepidium sativum husk powder with or without other pharmaceutical acceptable additive.
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The Lepidium sativum husk powder can be used in combination with different active pharmaceutical ingredients as super disintegrant. It can be (Lepidium seed husk) used extra-granularly in a range of 2 to 5 % of the total oral solid unit dosage form weight (tablets, capsules, pellets, powder for reconstitution etc).
It is found that, Lepidium sativum husk powder due to its favourably low hygroscopicity compared to known disintegrants is preferable choice for tablets containing moisture sensitive active pharmaceutical ingredients. Also for highly water soluble drugs, there is a problem of increase in disintegration time on storage with many of the available disintegrants. This problem will be minimum with Lepidium sathmm husk powder if used as a disintegrating agent.
The superiority of disintegration properties of the Lepidium sativum husk powder have been demonstrated in formulations containing various active pharmaceutical ingredients. It gives extra-ordinary performance when used extra granularly in a range of 2 to 5 %.
DETAILED DESCRIPTION OF INVENTION
According to present invention, use of Lepidium sativum husk powder a natural product as super-disintegrant has been studied and it has been demonstrated that it is comparable properties as superior synthetic superdisintegrant presently in use.
Studies to ascertain the disintegrants properties of Lepidium sativum husk powder were carried out as discussed hereunder :
[A] Physico-chemical evaluation of Lepidium sativum husk powder
(a) Hygroscopicity
Lepidium sativum husk powder, Croscarmelose sodium, Crospovidone and Sodium Starch Glycolate were taken in an individual petridish (5gm each), weighed the whole system and kept at 80 % (humidity) and 30°C for 30 days. The moisture gain was recorded by weighing the samples on 1st, 7th- 15th and 30th days. Percentage moisture gain at each interval was calculated.
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In this experiment it was found that Lepidium sativum husk powder was least hygroscopic with moisture gain of 15.69% at the end of 30 days at 80 % Relative humidity and 30°C temperature while sodium starch glycolate was the most hygroscopic material with moisture gain of 38.75%w/w as explained in figure 1.
(b) Ash values
Total ash: 7.17%
Acid insoluble ash: 1.53 %
(c) Moisture content of husk (By Karl Fischer Reagent) 1.834%
IB] Study of Lepidium sativum husk powder as super-disintegrant.
To study disintegration behavior of Lepidium sativum husk powder various oral, solid unit dosage forms with active ingredient from different classes having different physicochemical properties were prepared and evaluated for disintegration time
All the tablets were made using GMC 10 station, single rotary machine with D-tooling (Model no. JM-10). Tablet weight was determined by averaging the reading of 20 tablets weighed on 'Scaltech balance' (Model No. SBA 41 11905997). A Monsanto tablet hardness tester was used to determine the crushing strength of the tablets by averaging the readings of 5 tablets. Disintegration time were determined according to method (USP P. No.24 and NF 19, P.No. 1941) for uncoated tablets using water at 37°C ± 2°C, as the medium. The disintegration time were determined using Electrolab Tablet disintegration tester model ED-2L (USP) with 30 strokes per minutes.
All the formulation stored at ambient and accelerated temperature and humidity conditions shoes excellent storage stability.
(a) Effect of moisture content on the process of disintegration.
Moisture content of disintegrating agent is very important parameter because of the inherent moisture present inside the disintegrant affects its swelling behavior and therefore increases the disintegration time of the tablets.
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Table no. 1

Sr. No. Name of ingredient Formulation-A(mg) Formulation-B(mg) Formulation-C(mg)
1 Paracetamol 500.00 500.00 500.00
2 Pseudoephedrine Hydrochloride 30.00 30.00 30.00
3 Starch 44.00 44.00 44.00
4 Ac-di-sol 10.00 10.00 10.00
5 Starch 20.00 20.00 20.00
6 Polyvinylpyrrolidone K-30 2.00 2.00 2.00
7 Lepidium sativum husk powder with moisture content (1.8%) 20.00 -- ~
8 Lepidium sativum husk powder with moisture content (6.4%) — 20.00 ~
9 Aerosil 5.00 5.00 5.00
10 Talc 3.00 3.00 3.00
11 Magnesium stearate 3.00 3.00 3.00
Total 637.00 637.00 617.00
Manufacturing process
Starch, Paracetamol, Pseudoephedrine Hydrochloride and croscarmelose sodium were mixed in a planetary mixer. Polyvinylpyrrolidone K-30 was dissolved in boiling water, dispersed Starch was mixed in equal quantity of water and finally added to the above hot Polyvinylpyrrolidone K-30 solution and was mixed to obtain a translucent paste.
Dry mixed powder was granulated with the starch paste in the planetary mixer. The wet granules were dried in a fluidized bed dryer at 55°C till moisture content of 2.5 %. Dried granules were passed through 1mm (BSS, 16#) sieve and collected in a polybag.
All the lubricants and disintegrant if any, were passed through sieve no. 250mm (BSS 60#) and mixed with the above dried granules, compressed the blend on 12.5 mm round, flat faced beveled edged punches.
Table no. 2

Formulation Disintegration time (minutes) Hardness (Kg/cm2)
A 2.5 4 to 5
B 5.0 4 to 5
C 12.0 4 to 5
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Conclusion
The moisture content of the Lepidium sativum husk powder affects its performance. When Lepidium sativum husk powder used after drying, the disintegration time was found to be significantly lower than undried material.
(b) Effect of particle size on the process of Disintegration
Particle size of the husk is also one of the important parameters as far as its use as disintegrant in tablet formulation is concerned. Smaller particle size assures more uniform distribution of the disintegrant in the lubricated granules as well as the surface area of the particles increases tremendously, therefore when the disintegrant is exposed to water, it absorbs water quickly and results into bursting of tablet.
Table no. 3

Sr. No. Name of ingredient Formulation-A(mg) Formulation-B(mg) Formulation-C(mg)
1 Paracetamol 500.00 500.00 500.00
2 Pseudoephedrine Hydrochloride 30.00 30.00 30.00
3 Starch 44.00 44.00 44.00
4 Croscarmelose sodium 10.00 10.00 10.00
5 Starch 20.00 20.00 20.00
6 PVP K-30 2.00 2.00 2.00
7 lepidium sativum husk powder (250ujn) 20.00 — —
8 Lepidium sativum husk powder (150um) — 20.00 —
9 Aerosil 5.00 5.00 5.00
10 Talc 3.00 3.00 3.00
11 Magnesium stearate 3.00 3.00 3.00
Total 637.00 637.00 617.00
Manufacturing process
Starch, Paracetamol, Pseudoephedrine Hydrochloride and croscarmelose sodium were mixed in a planetary mixer. Polyvinylpyrrolidone K-30 was dissolved in boiling water, dispersed Starch was mixed in equal quantity of water and finally added to the above hot Polyvinylpyrrolidone K-30 solution and was mixed to obtain a translucent paste.
Dry mixed blend was granulated with this starch paste in the planetary mixer. The wet granules were dried in a fluidized bed dryer at 55°C till moisture content of 2 5 %
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obtained. Dried granules were passed through 1mm (BSS, 16#) sieve and collected in a polybag.
All the lubricants and disintegrant were passed if any through sieve no. 250mm (BSS, 60//) and mixed with the above dried granules, compressed the blend on 12.5 mm round, flat faced beveled edged punches.
Table no. 4

Formulations Disintegration time (minutes) Hardness (Kg/cm2)
A 2.5 4.0
B 1.0 4.0
C 12.0 4.00
Conclusion
As the particle size reduces, the surface area of disintegrating material increases and hence when exposed to aqueous media, quickly absorbs water and thereby results in rapid dissolution.
(c) Determination of concentration of disintegrant in the tablets
The concentration of disintegrant in the tablet dosage form should be established though it is variable and many time depends upon the nature of Active Pharmaceutical Ingredients. It is necessary to find out average concentration of the disintegrating agent sufficient to produce disintegration of respective tablet containing different active pharmaceutical ingredients.
Table no. 5

Sr. No. Name of Ingredients Formulation-A(mg) Formulation-B(mg) Formulation-C(mg)
1 Paracetamol 500.00 500.00 500.00
2 Polyvinylpyrrolidone K-30 5.00 5.00 5.00
3 Lepidium sativum husk powder 10.00 20.00 —
4 Aerosil 6.00 6.00 6.00
5 Talc 4.00 4.00 4.00
6 Magnesium stearate 5.00 5.00 5.00
Total 530.00 540.00 520.00
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Manufacturing process
Paracetamol was charged in a planetary mixer bowl. Polyvinylpyrrolidone K-30 was dissolved in Isopropyl alcohol. Paracetamol powder was granulated with Polyvinylpyrrolidone K-30 solution. Wet granules were dried in a fluidized bed dryer at 55°C till moisture content of 3.0% was obtained. Dried granules were sieved through 1mm (BSS 16 #) and collected in a polybag.
All the lubricants and disintegrant if any were sifted through 250 um (BSS 60#) and mixed with the above sieved granules. The blend was compressed on 12.5 flat faced, beveled edged punches.
Table no. 6

Formulation Disintegration time (minutes) Hardness (Kg/cm2)
A 7.00 3.00
B 1.00 3.00
C 20.00 3.00
Conclusion
From the experimentation it was found that Lepidium sativum husk powder works better in the range of 2.0 to 4.0 % and effects into rapid disintegration of tablets.
(d) Further experiments were carried out to prove the effectiveness of present disintegrating agent, in formulations and evaluating with different type of Active Pharmaceutical agents.
The details are provided by way of the following non-limiting exemplary illustrations:
Example 1 : Ciprofloxacin Hydrochloride Tablets
Ciprofloxacin Hydrochloride is an acidic drug, which is amorphous in nature. The drug is sparingly water-soluble. Because of these characteristics, it is difficult to make rapid disintegrating tablet of it, hence it is good candidate to evaluate disintegrating ability of any disintegrant. Ciprofloxacin Hydrochloride granules were mixed with the lubricants including disintegrant and compressed into tablets. Then the tablets were evaluated for disintegration and crushing strength.
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Table no. 7

Sr. No. Name of ingredient Qty. (mg)
1 Ciprofloxacin Hydrochloride 291.00
2 Disintegrant 9.00
3 Aerosil 3.00
4 Talc 3.00
5 Magnesium stearate 3.00
Total 309.00
Manufacturing process
Ciprofloxacin Hydrochloride powder was charged in a planetary mixer bowl and was granulated with water. Wet granules were dried in a fluidized bed dryer at 50°C for 30 minutes. Dried granules were sifted through 1mm (BSS 16#) and collected in a polybag.
All the lubricants and disintegrants if any were sifted through 250mm (BSS 60#) and mixed with the dried granules. The blend was compressed on 10.0 mm standard concave round punches. Then the tablets were evaluated for disintegration time and crushing strength.
Table no. 8

Disintegrant Disintegration time Hardness (Kg/cm2)
Without disintegrant 14.00 minutes 5.00
Lepidium sativum husk powder 2.00 minutes 5.00
Crospovidone 1.00 minute 30 Sec. 5.00
Croscarmelose sodium 1.00 minute 30 Sec. 6.00
Sodium Starch Glycolate 2.00 minute 30 Sec. 6.00
Conclusion:
The disintegrating time when compared for all disintegration shows that Lepidium sativum husk powder is equally effective to that of Crospovidone, Croscarmelose sodium and it can be called as super-disintegrant.
Example- 2: Mefenamic acid tablets
Active Pharmaceutical Ingredients like Mefenamic acid which is highly hydrophobic in nature was taken as example to find out efficacy of the disintegrant Lepidium sativum husk powder.
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Table no. 9

Sr. No. Name of ingredient Oty. (mg)
1 Mefenamic acid 500.00
2 Starch 75.00
3 PVP K-90 F 12.00
4 Propylene glycol 10.00
5 Disintegrant 21.00
6 MCC DC Grade 86.00
7 Aerosil 5.00
8 Magnesium stearate 2.00
9 Talc 10.00
Total 721.00
Manufacturing process
Mefenamic acid powder was charged in a planetary mixer bowl. Starch was dispersed in equal quantity of water, Polyvinylpyrrolidone K-90F was dissolved in 200ml of boiling water and Propylene glycol was added into it and mixed. Then the starch slurry was added and mixed to form Starch Paste of uniform consistency.
The above Starch paste was then added to the Mefenamic acid powder in the planetary mixer bowl and mixed to obtain uniform granules. Wet granules were dried in a fluidized bed dryer at 55°C for 1 hr. Dried granules were passed through 1mm (BSS 16#) and collected in a polybag. All the lubricants and disintegrants if any are sifted through 250u,m, (BSS 60#) and mixed with equivalent amount of granules. The blend was compressed on 17.9 X 7.8 mm standard concave, capsule shaped punch.
These tablets were then evaluated for hardness and disintegration time, using standard calibrated equipments.
Table no. 10

Disintegrant Disintegration time (minutes) Hardness (Kg/cm2)
Without disintegrant 14.00 7.00
Sodium Starch Glycolate 6.00 7.00
Crospovidone 5.00 7.00
Croscarmelose sodium 6.00 7.00
Lepidium sativum husk powder 6.00 7.00
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Conclusion : When the trials were taken with different disintegrating agents, it was found that the disintegration time was of the order of 5 to 6 minutes and the disintegration time with Lepidium sativum husk powder was comparable to those with Crospovidone, Croscarmelose sodium, sodium starch glycolate at equal hardness.
Example - 3 : Amoxycillin Tablets
Antibiotics like semi-synthetic penicillin have very typical powder characteristics. The powder contains inbuilt moisture as water of hydration as well as the powders are non-flowing therefore they have either to be compacted or wet granulated before final compression stage. This has been elaborated in the following example.
Table no. 11

Sr. No. Name of ingredient Qty.(mg)
1 "Amoxycillin Trihydrate IP equivalent to Amoxycillin 290.00
2 Polyvinylpyrrolidone K-90F 5.00
3 Isopropyl alcohol q.s.
4 Disintegrant 9.50
5 Colloidol silicon dioxide 5.50
6 Talc 5.00
7 Magnesium stearate 3.00
Total 318.00
Manufacturing procedure
Amoxycillin trihydrate powder was charged into planetary mixer bowl. Polyvinylpyrrolidone K-90F was dissolved into isopropyl alcohol and the amoxycillin trihydrate powder was granulated with Polyvinylpyrrolidone K-90F binder solution in the planetary mixer. Wet granules were dried in a fluidized bed dryer at 35°C for 1 hr., The dried granules were passed through 1mm (BSS 16#) and collected in a polybag.
All the lubricants and disintegrant if any were sifted, through 250^m (BSS 60#) and mixed with equivalent amount of amoxycillin granules. This blend was compressed on 9.00 mm flat faced beveled edges punches.
The above manufactured tablets were evaluated for disintegration test as well as crushing strength using standard equipments. Following are the results of evaluation.
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Table no. 12

Disintegrant Disintegration time Hardness (Kg/cm2)
Without disintegrant 25 minutes 4 to 5
Sodium Starch Glycolate 108 seconds 4 to 5
Crospovidone 70 seconds 4 to 5
Croscarmelose sodium 100 seconds 4 to 5
Lepidium sativum husk powder 100 seconds 4 to 5
Conclusion :
The tablets without any disintegrating agent was showing maximum disintegration time because there was no bursting / wicking'/ swelling in the tablet structure for long time. But when the similar tablets were compressed with disintegrating agents like Lepidium sativum husk powder, crospovidone, sodium starch glycolate or croscarmelose sodium, it was rapidly disintegrating. The performance of Lepidium sativum husk powder was at par with different superdisintegrants under study. From this experiment it can also be concluded that Lepidium sativum husk powder works well with active pharmaceutical ingredients having high percentage of water of hydration.
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Example - 4 Cephalexin Tablets
Cephalosporins are modified penicillins and therefore almost have similar powder characteristics. The powders are moisture sensitive and hence can only be wet granulated with non-aqueous solvents like isopropyl alcohol and similar solvents and must be dried at low temperature.
Table no. 13

Sr. No. Name of ingredient Oty. (mg)
1 Cephalexin 265.67
2 Polyvinylpyrrolidone K-90F 5.00
Isopropyl alcohol q.s.
4 Disintegrant 9.00
5 Magnesium stearate 3.00
6 Talc 3.33
7 Colloidal silicon dioxide 4.00
Total 290.00
Manufacturing procedure
Cephalexin powder was charged into planetary mixer bowl. Polyvinylpyrrolidone K 90 F was dissolved into isopropyl alcohol and granulated the Cephalexin powder with the PVP K-90F solution. Wet granules were dried in a fluidized bed dryer at 35°C for 30 min. The dried granules were passed through 1 mm (BSS,16#) and collected in a polythene bag.
All the lubricants and disintegrant if any were sifted, through 250mm (BSS, 60#) and mixed with equivalent quantity of cephalexin granules. Compressed this blend on 9.00 mm flat faced beveled edges punches. Evaluated these tablets for disintegration time and hardness tests, using standard equipments.
Table no. 14

Disintegrant Disintegration time Hardness (Kg/cm2)
Without Disintegrant 6 minutes 4 to 5
Crospovidone 70 seconds 4 to 5
Croscarmelose sodium 50 seconds 4 to 5
Lepidium sativum husk powder 70 seconds 4 to 5
Sodium starch glycolate 80 seconds 4 to 5
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[C] Superdisintegrant with viscosity building property
Sedimentation studies are conducted to find out usefulness of the material in dispersible tablets wherein tablet is required to disintegrate in vitro in limited amount of water and then the suspension thus found is administered orally.
In this kind of dosage forms addition of viscosity building agent is forbidden from formulation point of view as it imparts excessive binding to the dosage form. But in this case use of novel natural superdisintegrant with viscosity building properties is advantageous. To prove the point following experiment was carried out.
a) Sedimentation study
Each material under study (lg each) was taken and mixed with 9.0 g of micrecrystalline cellulose in a pestie mortar. In the 100 ml measuririgcylinder 3.0 g of the above mixture was taken. To it distilled water was added up to the mark, and the contents were mixed vigorously. The suspension was allowed to settle at room temperature for about 10 minutes. The volume of settled material was noted after each 2 minutes' interval.
From the results (figure 2), it is clearly evident that Lepidium sativum husk powder helps in keeping microcrystalline cellulose in suspended form for much longer duration than other super-disintegrant. This property enables it to act like a suspending agent upon disintegration. Thus it serves dual purpose in dispersible tablets, first as disintegrant and later on as suspending agent. The material is unique in this regard, since no material presently in used by pharmaceutical industry possesses these properties.
b) Lepidium sativum husk powder in dispersible solid dosage forms
Various formulations containing different pharmaceutical therapeutic agents and Lepidium sativum husk powder were formulated in dispersible solid dosage forms and their performance was evaluated in comparison with existing superdisintegrants. Sedimentation study was also performed on formulated dispersible solid dosage forms. The details are provided hereunder by way of following further non-limiting exemplary illustrations :
Example - 5: Diclofenac sodium tablets
Diclofenac sodium is very well known non steroidal anti-inflammatory drug useful especially in pain associated with rheumatoid arthritis. It acts quickly by the mechanism of
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inhibition of cyclooxygenase, but when the drug is compressed into tablets, the effect depends upon release of the drug from the tablet. Here is the role of superdisintegrant comes into picture. The more efficient the disintegrant, the more quicker will be the release of drug from tablets and therefore results into faster therapeutic action. Therefore the need of super disintegrant is generated and search for it is still going on.
Diclofenac sodium is water soluble, white fine powder having good compressibility characteristics, but due to water soluble nature of the drug, the tablet disintegrates by the mechanism of erosion and not by swelling or wicking. Following is the example where all known superdisintegrants are used along with Lepidium sativum husk powder and compared the disintegration time at constant hardness.
Table no. 15

Sr. No. Name of ingredient Qty.(mg)
1 Diclofenac Sodium 50.00
2 Lactose 112.00
3 Starch 4.00
4 Purified water q.s.
5 Disintegrant 6.00
6 Colloidol silicon dioxide 3.00
7 Talc 3.00
8 Magnesium stearate 2.00
180.00
Manufacturing process:
Weighed quantity of Diclofenac sodium and Lactose were charged in a planetary mixer bowl and mixed for 5 minutes. Starch was dispersed in equal quantity of water; boiled water equivalent to four times the water used for slurry preparation was added. Starch slurry was added to the boiled water and stirred to effect smooth paste.
The dry mix of planetary mixer was granulated with starch paste. The wet granules were dried in fluidized bed dryer at 50°C for 30 minutes. The dried granules were passed through 1mm (BSS, 16#) and collected in a polybag.
All the lubricants and disintegrants if any were sifted through 250 mm (BSS, 60#) and mixed with equivalent quantity of granules in a polybag. The blend was compressed on 8.0 mm flat faced, round, beveled edged punches.
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These tablets were evaluated for hardness and disintegration time.
Table no. 16

Disintegrant Disintegration time Hardness (Kg/cm2)
Without disintegrant 180 minutes 2.5 to 3.5
Crospovidone 120 seconds 2.5 to 3.5
Croscarmelose sodium 130 seconds 2.5 to 3.5
Lepidium sativum husk powder 140 seconds 2.5 to 3.5
Sodium starch glycolate 150 seconds 2.5 to 3.5
Conclusion
It is known to those who are skilled in the art, that presence of soluble diluents like Lactose, the disintegration time of tablets get affected, but diluents like Lactose which are inert in nature are widely accepted and having good flow and compression properties. Therefore, bnly superdisintegrating agent can reduce the disintegration time of these tablets. This is proved in the above experiment.
Lepidium sativum husk powder though used in low concentration of 3.0% results in rapid disintegration, which is comparable to that of superdisintegrants, like crospovidone, croscarmelose sodium and sodium starch glycolate.
Example - 6 : Cephalexin 250 mg dispersible tablets
Table no. 17

Sr. No. Name of ingredient Qty.(mg) Qty. (mg) Qty. (mg) Qty. (mg)
1 Cephalexin 266.00 266.00 266.00 266.00
2 Starch 90.00 90.00 90.00 90.00
3 Microcrystalline cellulose 80.00 80.00 80.00 80.00
4 Colloidal silicon dioxide 5.00 5.00 5.00 5.00
5 Polyvinylpyrrolidone K-30 21.00 21.00 21.00 21.00
6 Colloidal silicon dioxide 5.00 5.00 5.00 5.00
7 Magnesium stearate 4.00 4.00 4.00 4.00
8 Talc 6.00 6.00 6.00 6.00
9 Flavour 8.00 8.00 8.00 8.00
10 Sodium saccharine 10.00 10.00 10.00 10.00
11 Crospovidone 20.00 — — —
12 Croscarmelose sodium « 25.00 — —
13 Sodium starch glycolate — — 35.00 ~
14 Lepidium sativum husk powder — — — 20.00
Total 500.00 505.00 515.00 500.00
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Manufacturing process
Cephalexin, starch, microcrystalline cellulose and Colloidal silicon dioxide were passed through 500mm (BSS, 30#) sieve and mixed well. Polyvinylpyrrolidione K-30 was dissolved in Isopropyl alcohol. Above blend was granulated with this binder solution and dried in Fluidized Bed Dryer at 35°C for 30 minutes or moisture content was 1.5%. Granules were passed to 500 mm (BSS, 30#) sieve. The above granules were lubricated using colloidal silicon dioxide, magnesium stearate, talc and disintegrant if any and mixed well. All lubricants were previously passed through 500mm (BSS, 30#) sieve. Finally flavour and sodium saccharine (250mm, BSS 60 #) were added and mixed well.
The blend was compressed using 11.2 mm flat-faced, beveled punches and tablets were evaluated for disintegration time, hardness, viscosity and sedimentation study. (Table; 18, Fig 3). For viscosity study 40 tablets were added in 200 ml of water, allowed to disperse completely and viscosity of resultant suspension was measured using Brookfield viscometer (LVF Model) at 250C„ 30rpm, spindle no. 2.
Table no. 18

Disintegrant Disintegration time (seconds) Hardness (Kg/cm2) Viscosity (cp)
Without disintegrant 240.00 5.00
Sodium Starch Glycolate 120.00 5.00 10
Crospovidone 120.00 5.00 12
Croscarmelose sodium 120.00 5.00 10
Lepidium sativum husk powder 95.00 5.00 140
Example- 7 : Roxithromycin 50 mg dispersible tablets
Table no. 19

Sr. No. Name of ingredient Qty. (mg) Qty. (mg) Qty. (mg) Qty. (mg)
1 Roxithromycin 50.00 50.00 50.00 50.00
2 Aspartame 29.00 29.00 29.00 29.00
3 Microcrystalline cellulose 53.00 53.00 53.00 53.00
4 Colloidal silicon dioxide 4.00 4.00 4.00 4.00
5 Polyvinylpyrrolidone K-30 4.00 4.00 4.00 4.00
6 Colloidal silicon dioxide 4.00 4.00 4.00 4.00
7 Magnesium stearate 3.00 3.00 3.00 3.00
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8 Microcrystalline Cellulose (directly compressible) 200.00 200.00 200.00 200.00
9 Flavour 8.00 8.00 8.00 8.00
10 Crospovidone — 20.00 ~ . ~
11 Croscarmelose sodium 20.00 — — —
12 Sodium starch glycolate — — 30.00 —
13 Lepidium sativum husk powder powder — — ~ 20.00
Total 215.00 215.00 225.00 215.00
Manufacturing process
Roxithromycin, Aspartame, microcrystalline cellulose and Colloidal silicon dioxide were passed through 500mm (BSS, 30#) sieve and mixed well. Polyvinylpyrrolidione K-30 was dissolved in Isopropyl alcohol Above blend was granulated with this binder solution and dried in Fluidized Bed Dryer at 35°C for 30 minutes or till moisture content was 1.0%. Granules were passed to 500 mm (BSS, 30#) sieve, the above granules were lubricated using colloidal silicon dioxide, magnesium stearate and microcrystalline cellulose (directly compressible) and disintegrant if any and mixed well. All lubricants were previously passed through 500mm (BSS, 30#) sieve. Finally flavour (250mm, BSS 60 #) was added and mixed well.
The blend was compressed using 10.0 mm flat-faced, beveled punches and tablets were evaluated for disintegration time, hardness, viscosity and sedimentation study. (Table 20, Fig 4) For viscosity study 40 tablets were added in 200 ml of water, allowed to disperse completely and viscosity of resultant suspension was measured using Brookfield viscometer (LVF Model) at 25°C, 30rpm, spindle no. 2.
Table no. 20

Disintegrant Disintegration time (seconds) Hardness (Kg/cm2) Viscosity (cp)
Without disintegrant 270.00 5.5
Sodium Starch Glycolate 80.00 5.5 10
Crospovidone 70.00 5.5 8
Croscarmelose sodium 60.00 5.5 10
Lepidium sativum husk powder 40.00 5.5 144
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Example - 8 : Diclofenac sodium 50.00 mg dispersible tablets
Table no. 21

Sr. No. Name of ingredient Qty. (mg) Qty.(mg) Qty. (mg) Qty. (mg)
1 Diclofenac sodium 50.00 50.00 50.00 50.00
2 Microcrystalline cellulose 50.00 50.00 50.00 50.00
-> j Polyvinylpyrrolidone K-30 3.00 3.00 3.00 3.00
4 Purified water q.s q.s. q.s. q.s.
5 Colloidal silicon dioxide 4.00 4.00 4.00 4.00
6 Microcrystalline Cellulose (directly compressible) 41.00 41.00 41.00 41.00
7 Flavour 5.00 5.00 5.00 5.00
8 Aspartame 6.00 6.00 6.00 6.00
9 Magnesium stearate 2.00 2.00 2.00 2.00
10 Croscarmelose sodium 9,00 _. ~ ~
11 Sodium starch glvcolate — — 15.00
12 Crospovidone - — 9.00 —
13 epzpidium sativum husk powder powder — 5.00 ~ —
Total 170.00 166.00 170.00 176.00
Manufacturing process
Diclofenac sodium and microcrystalline cellulose were passed through 500mm (BSS, 30#) sieve and mixed well. Polyvinylpyrrolidione K-30 was dissolved in water. Above blend was granulated with this binder solution and dried in Fluidized Bed Dryer at 35°C till the moisture content of the granules was 1.5%. Granules were passed to 500 u,m (BSS, 30#) sieve. The above granules were lubricated using colloidal silicon dioxide, magnesium stearate, Microcrystalline cellulose (directly compressible), flavour, aspartame and disintegrant (if any). All lubricants were previously passed through 250mm (BSS, 60#) sieve, except microcrystalline cellulose (directly compressible), which was passed through 500n (BSS, 30#).
The blend was compressed using 8.0 mm flat-faced, beveled punches and tablets were evaluated for disintegration time, hardness, viscosity and sedimentation study (Table 22, Fig 5) For viscosity study 40 tablets were added in 200 ml of water, allowed to disperse completely and viscosity of resultant suspension was measured using Brookfield viscometer (LVF Model) at 25°C, 30rpm, spindle no. 2.
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Table no. 22

Disintegrant Disintegration time (seconds) Hardness (Kg/cm2) Viscosity (cp)
Without disintegrant 660.00 2.00 —
Sodium Starch Glycolate 82.00 2.00 8
Crospovidone 80.00 2.00 10
Croscarmelose sodium 75.00 2.00 8
Lepidium sativum husk powder 60.00 2.00 120
Example - 9 : Cefadroxil 125 mg dispersible tablets
Table no. 23

Sr. No. Name of ingredient Qty. (mg) Qty. (mg) Qty. (mg) Qty. (mg)
1 Cefadroxil 132.5 132.5 132.5 132.5
2 Aspartame 6.00 6.00 6.00 6.00
3 Microcrystailine cellulose 50.5 30.5 50.5 50.5
4 Polyvinylpyrrolidone K-30 2.00 2.00 2.00 2.00
5 Isopropyl alcohol q.s. q.s. q.s. q.s.
6 Colloidal silicon dioxide 3.00 3.00 3.00 3.00
7 Magnesium stearate 2.00 2.00 2.00 2.00
8 Flavour 4.00 4,00 4.00 4.00
9 Crospovidone 6.00 — — —
10 Croscarmelose sodium __ 7.00 — —
11 Sodium starch glycolate ~ r- 10.00 ~
12 Lepidium sativum husk powder -- — — 6.00
Total 206.00 207.00 210.00 206.00
Manufacturing process
Cefadroxil, microcrystalline cellulose and aspartame were passed through 500mm (BSS, 30#) sieve and mixed well. Polyvinylpyrrolidione K-30 was dissolved in isopropyl alcohol. Above blend was granulated with this binder solution and dried in Fluidized Bed Dryer at 35°C till the moisture content of the granules was 1.0%. Granules were passed through 500 mm (BSS, 30#) sieve. The above granules were lubricated using colloidal silicon dioxide, flavour, magnesium stearate, and disintegrant (if any). All lubricants were previously passed through 250mm (BSS, 60#) sieve!
The blend was compressed using 8.0 mm flat faced beveled punches and tablets were evaluated for disintegration time, hardness, viscosity and sedimentation study. (Table 24, Fig 6) For viscosity study 40 tablets were added in 200 ml of water, allowed to disperse
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completely and viscosity of resultant suspension was measured using Brookfield viscometer (LVF Model) at 25°C, 30rpm, spindle no. 2.
Table no. 24

Disintegrant Disintegration time (seconds) Hardness (Kg/cm2) Viscosity (cp)
Without disintegrant 98.00 2.00
Sodium Starch Glycolate 85.00 2.00 8
Crospovidone 55.00 2.00 10
Croscarmelose sodium 42.00 2.00 10
Lepidium sativum husk powder 25.00 2.00 128
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WE CLAIM
1. A process for preparing a pharmaceutical composition in solid dosage form comprising mixing at least one pharmaceutical therapeutic agent in the form of dried granules with Lepidium sativum husk powder as distintegrating agent with or without other pharmaceutical^ acceptable additive and thereafter compressing and/or further processing the mixture in a conventional manner to get the tablets and/or capsules.
2. A process for preparing pharmaceutical composition as claimed in claim 1, wherein the said Lepidium Sativium husk powder has a particle size in the range of 100u to 250u.
3. A process for preparing pharmaceutical composition as claimed in claims 1 and 2, wherein said Lepidium Sativum husk powder has a particle size in the range of 100u to 200u.
4. A process for preparing pharmaceutical composition as claimed in claims 1 to 3, wherein said Lepidium Sativum husk powder has moisture content in the range of of 1.5% to 2.5%;
5. A process for preparing pharmaceutical composition as claimed in any preceding claim wherein said therapeutic agent is selected from a group of acidic, basic or neutral compounds having discriminating solubility ranging from highly soluble to practically insoluble in aqueous vehicle.
6. A process for preparing pharmaceutical composition as claimed in anyone of claims 1 to 5 wherein said acidic, basic or neutral pharmaceutical therapeutic agents are selected from ciprofloxacin hydrochloride, paracetamol, pseudoephedrine Hydrochloride, amoxycilline Trihydrate, cephalexin, mefenamic acid.
7. A process for preparing pharmaceutical composition as claimed in anyone of claims 1 to 6 wherein said Lepidium sativium husk powder present in the range of 2.0 to 5.0% of the total weight of the solid dosage forms.
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8. A process for preparing pharmaceutical composition as claimed in anyone of claims 1 to 7 wherein the Lepidium sativium husk powder has particle size of between 100u to 250u.
9. A process for preparing pharmaceutical composition as claimed in claim 8 wherein said Lepidium sativium husk powder have particle size of 150u
10. A process for preparing pharmaceutical composition as claimed in claim 9 in solid
dosage form for pediatric and geriatric formulations.
11. A process for preparing pharmaceutical composition as claimed in claim 10 wherein said therapeutic agent is selected from a group of acidic, basic or neutral compounds having discriminating solubilities ranging from highly soluble to practically insoluble in aqueous vehicle.
12. A process for preparing pharmaceutical composition as claimed in claim 10 or 11 wherein said therapeutic agents are selected from roxithromycin, cefadroxil, cephalexin, diclofenac sodium.
13. A process for preparing pharmaceutical composition as claimed in anyone of claims 10 to 12 comprising said Lepidium sativum husk powder in the range of 2.0 to 5.0% of the total weight of the solid dosage form.
14. A process for preparing pharmaceutical composition as claimed in anyone of claims 10 to 13 wherein said Lepidium sativium husk powder, having particle size between 250u to 100u preferably 150u.
15.A process for preparing pharmaceutical composition in solid dosage form substantially as herein described and illustrated in the samples.

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ABSTRACT
A novel disintegrant for pharmaceutical preparations comprising Lepidium sativum husk powder having a particle size in the range of l00m to 250m.Preferably the moisture content of the husk powder is in the range of 1.5 to 2.5% .Also disclosed is pharmaceutical composition comprising in solid dosage form atleast one pharmaceutical therapeutic agent and the Lepidium sativum husk powder with or without other pharmaceutical acceptable additive. The Lepidium sativum husk powder can be used in combination with different active pharmaceutical ingredients as super disintegrant. It can be (Lepidium seed husk) used extra-granularly in a range of 2 to 5 % of the total oral solid unit dosage form weight as tablets, capsules, pellets, powder for reconstitution etc. The novel disintegrant is of natural origin and does not involve the modifications and/or complexity in manufacture of synthetic disintegrants presently in use. It is safe and can be made easily available as a cost-effective disintegrant. It serves as a novel disintegrant as well as viscosity building agent for use in tablet, capsule or pellet dosage forms. It can be used as a disintegrating agent with wide variety of pharmaceutical compositions containing different kind of pharmaceutical therapeutic agent namely acidic, basic or neutral having different solubilities ranging from highly soluble to practically insoluble molecules. The novel disintegrating agent have comparable disintegrating properties as that of various super disintegrants currently used by the pharmaceutical industry.


To
The Controller of Patent The Patent Office At Mumbai

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