The present disclosure relates generally to orodispersible tablets of metformin. More specifically, the disclosure is directed to an orodispersible tablet formulation comprising metformin hydrochloride and Cajanus cajan starch as a super-disintegrant. The disclosure further provides a process of preparing the formulation.
BACKGROUND OF THE INVENTION
[0002] Background description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art. [0003] Active substances can be transported to the desired site of action safely and effectively through various drug delivery routes such as oral, parenteral, transdermal and topical administrations. Oral administration is the most common route of all these due to its benefits such as the ability to self-administer, no pain, high patient compliance, high-dose drug administration, well-controlled scale-up procedures, and versatility in the dosage form design. Amongst the dosage forms, solid dosage forms are frequently administered and the most common solid dosage forms are tablets and capsules. Some patients have inconvenience in swallowing tablets and capsules which becomes a disadvantage. Nowadays, tablets that dissolve rapidly in the oral cavity have become quite common. Orodispersible tablets (ODTs) signify a rapidly evolving method of drug delivery with high patient compliance. For individuals with swallowing problems, or for patients with dysphasia, ODTs are beneficial. The disintegration time of ODTs is less than a minute. They have high bioavailability because as the saliva passes down the stomach, the absorption of drugs from the mouth, pharynx, and oesophagus follows. In both industry and academia, the benefits of ODTs are being increasingly recognized.
[0004] ODTs require specific excipients to be included with the API. Natural excipients are more beneficial than synthetic excipients because they are easily

available, eco-friendly, biologically acceptable, and cost efficient as compared to imported synthetic products.
[0005] The anti-hyperglycemic drug metformin hydrochloride belongs to the biguanide family of medicines. Metformin is currently the first-line therapy for type 2 diabetes. Metformin hydrochloride has high water solubility and poor cell membrane permeability and belongs to BCS type III class. The high dosage of metformin, on the other hand, necessitates a large tablet size, which decreases compliance among elderly patients due to swallowing difficulties. Metformin hydrochloride may be formulated into an orodispersible tablet to increase its patient compliance provided suitable excipients are devised for the formulation. [0006] Thus, there is a need in the art to formulate orodispersible tablet formulations of metformin hydrochloride with suitable excipients.
OBJECTS OF THE INVENTION
[0007] An object of the present disclosure is to provide an orodispersible tablet formulation of metformin hydrochloride with a natural super-disintegrant. [0008] An object of the present disclosure is to provide an orodispersible tablet formulation comprising metformin hydrochloride and Cajanus cajan starch as a natural super-disintegrant.
[0009] An object of the present disclosure is to provide an orodispersible tablet formulation that has low in vitro disintegration time, high water absorption ratio and low wetting time.
SUMMARY OF THE INVENTION
[0010] This summary is provided to introduce a selection of concepts in a simplified form that are further described below in Detailed Description section. This summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended to be used as an aid in determining the scope of the claimed subject matter.
[0011] Aspects of the present disclosure relate to an orodispersible tablet formulation, for the BCS II drug - metformin hydrochloride, that improves

bioavailability and patient compliance of the drug. A natural super-disintegrant
has been explored specifically polysaccharide obtained from Cajanus cajan or
Pigeon pea.
[0012] In an aspect, the present disclosure provides an orodispersible tablet
formulation comprising metformin hydrochloride and Cajanus cajan starch.
[0013] In an embodiment, the formulation comprises metformin hydrochloride in
a weight range of about 85% to about 90% w/w with respect to the formulation.
[0014] In an embodiment, the formulation comprises Cajanus cajan starch in a
weight range of about 1.5% to about 6% w/w with respect to the formulation.
[0015] In an embodiment, the Cajanus cajan starch is obtained from Cajanus
cajan seeds.
[0016] In an embodiment, the Cajanus cajan starch is microwave modified
Cajanus cajan starch.
[0017] In an embodiment, the formulation further comprises a pharmaceutically
acceptable excipient.
[0018] In an aspect, the present disclosure provides a process of manufacturing an
orodispersible tablet formulation comprising the steps of: (a) extracting Cajanus
cajan starch from Cajanus cajan seeds; (b) optionally modifying the Cajanus
cajan starch by microwave heating; (c) mixing the Cajanus cajan starch with
metformin hydrochloride and a pharmaceutically acceptable excipient; and (d)
compressing to form the tablet formulation.
[0019] In an aspect, the present disclosure provides a medicament comprising the
orodispersible tablet formulation.
[0020] Other aspects of the invention will be set forth in the description which
follows, and in part will be apparent from the description, or may be learnt by the
practice of the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
[0021] The following drawings form part of the present specification and are included to further illustrate aspects of the present disclosure. The disclosure may

be better understood by reference to the drawings in combination with the detailed
description of the specific embodiments presented herein.
Figure 1 provides a FTIR spectrum of pure drug metformin hydrochloride.
Figure 2 provides a FTIR spectrum of a formulation comprising microwave
modified Cajanus cajan starch and metformin hydrochloride, as per an
embodiment of the present disclosure.
Figure 3 provides graphically the in vitro cumulative %drug release profiles of
orodispersible tablet formulations, ODF1 to ODF9, as per an embodiment of the
present disclosure.
DETAILED DESCRIPTION OF THE INVENTION
[0022] The following is a detailed description of embodiments of the
disclosure. The embodiments are in such detail as to clearly communicate the disclosure. However, the amount of detail offered is not intended to limit the anticipated variations of embodiments; on the contrary, the intention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the present disclosure as defined by the appended claims.
[0023] All publications herein are incorporated by reference to the same
extent as if each individual publication or patent application were specifically and
individually indicated to be incorporated by reference. Where a definition or use
of a term in an incorporated reference is inconsistent or contrary to the definition
of that term provided herein, the definition of that term provided herein applies
and the definition of that term in the reference does not apply.
[0024] Reference throughout this specification to "one embodiment" or "an
embodiment" means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0025] In some embodiments, numbers have been used for quantifying
weight, percentages, ratios, and so forth, to describe and claim certain embodiments of the invention and are to be understood as being modified in some instances by the term "about." Accordingly, in some embodiments, the numerical parameters set forth in the written description and attached claims are approximations that can vary depending upon the desired properties sought to be obtained by a particular embodiment. In some embodiments, the numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as practicable. The numerical values presented in some embodiments of the invention may contain certain errors necessarily resulting from the standard deviation found in their respective testing measurements.
[0026] Various terms as used herein are shown below. To the extent a term
used in a claim is not defined below, it should be given the broadest definition persons in the pertinent art have given that term as reflected in printed publications and issued patents at the time of filing.
[0027] As used in the description herein and throughout the claims that
follow, the meaning of "a," "an," and "the" includes plural reference unless the context clearly dictates otherwise. Also, as used in the description herein, the meaning of "in" includes "in" and "on" unless the context clearly dictates otherwise.
[0028] Unless the context requires otherwise, throughout the specification
which follow, the word "comprise" and variations thereof, such as, "comprises" and "comprising" are to be construed in an open, inclusive sense that is as "including, but not limited to."
[0029] The recitation of ranges of values herein is merely intended to serve
as a shorthand method of referring individually to each separate value falling

within the range. Unless otherwise indicated herein, each individual value is
incorporated into the specification as if it were individually recited herein.
[0030] All methods described herein can be performed in any suitable order
unless otherwise indicated herein or otherwise clearly contradicted by context.
The use of any and all examples, or exemplary language (e.g. "such as") provided
with respect to certain embodiments herein is intended merely to better illuminate
the invention and does not pose a limitation on the scope of the invention
otherwise claimed. No language in the specification should be construed as
indicating any non-claimed element essential to the practice of the invention.
[0031] Groupings of alternative elements or embodiments of the invention
disclosed herein are not to be construed as limitations. Each group member can be referred to and claimed individually or in any combination with other members of the group or other elements found herein. One or more members of a group can be included in, or deleted from, a group for reasons of convenience and/or patentability. When any such inclusion or deletion occurs, the specification is herein deemed to contain the group as modified.
[0032] The description that follows, and the embodiments described therein,
is provided by way of illustration of an example, or examples, of particular embodiments of the principles and aspects of the present disclosure. These examples are provided for the purposes of explanation, and not of limitation, of those principles and of the disclosure.
[0033] It should also be appreciated that the present disclosure can be
implemented in numerous ways, including as a system, a method or a device. In
this specification, these implementations, or any other form that the invention may
take, may be referred to as processes. In general, the order of the steps of the
disclosed processes may be altered within the scope of the invention.
[0034] The headings and abstract of the invention provided herein are for
convenience only and do not interpret the scope or meaning of the embodiments. [0035] The following discussion provides many example embodiments of the inventive subject matter. Although each embodiment represents a single combination of inventive elements, the inventive subject matter is considered to

include all possible combinations of the disclosed elements. Thus if one
embodiment comprises elements A, B, and C, and a second embodiment
comprises elements B and D, then the inventive subject matter is also considered
to include other remaining combinations of A, B, C, or D, even if not explicitly
disclosed.
[0036] As used herein, the term 'management' refers to the treatment, alleviation
or prevention of diabetes mellitus; or lowering, arresting or controlling of blood
sugar levels in a subject.
[0037] The term, "subject" as used herein refers to an animal, preferably a
mammal, and most preferably a human. The term "mammal" used herein refers to
warm-blooded vertebrate animals of the class 'mammalia' , including humans,
characterized by a covering of hair on the skin and, in the female, milk-producing
mammary glands for nourishing the young, the term mammal includes animals
such as cat, dog, rabbit, bear, fox, wolf, monkey, deer, mouse, pig and human.
[0038] As described herein, the term 'effective amount' refers to the amount of
the formulation required to manage diabetes mellitus in a subject without causing
side effects or overdosing.
[0039] The terms 'orodispersible tablet' and 'oral dispersible tablet' have been
used interchangeably throughout the specification.
[0040] Cajanus cajan (Pigeon Pea, Syn. Cajanus indicus) belongs to the family
Fabaceae. Its roots are most likely in Asia, from where it migrated to East Africa
and then to the American continent through slave trade. It has been studied in the
treatment of ischemic necrosis of the caput femoris, aphtha, bedsores, and wound
healing. For several years, it has been commonly used to treat diabetes, sores, skin
irritations, hepatitis, measles, jaundice, dysentery, and a number of other diseases,
as well as to remove bladder stones and control the menstrual cycle.
[0041] Aspects of the present disclosure explore the starch of Cajanus cajan as a
super-disintegrant for an oral dispersible tablet (ODT) formulation comprising
metformin.
[0042] In an embodiment, the present disclosure provides an orodispersible tablet
formulation comprising metformin hydrochloride and Cajanus cajan starch.

[0043] In an embodiment, the formulation comprises metformin hydrochloride in a weight range of about 85% to about 90% w/w with respect to the formulation. [0044] In an embodiment, the formulation comprises Cajanus cajan starch in a weight range of about 1.5% to about 6% w/w with respect to the formulation. [0045] In an embodiment, the Cajanus cajan starch is obtained from Cajanus cajan seeds.
[0046] In some embodiments, the Cajanus cajan starch is microwave modified starch. In some embodiments, the microwave modified starch is starch modified by microwave assisted method by exposing a solution of the starch at about 70°C to about 150°C for about 2 minutes to about 5 minutes at a power of about 800 W. [0047] In some embodiments of the present disclosure, the tablets, when taken orally, can disintegrate and dissolve rapidly in the buccal cavity of the subject. Upon disintegration and dissolution, absorption of active agent can occur in the buccal cavity of the subject.
[0048] In an embodiment, the formulation further comprises a pharmaceutically acceptable excipient. In an embodiment, the excipient may be selected from carrier, preservative, flavoring agent, coloring agent, diluent, sweetener, solvent, stabilizer, lubricant, glidant, anti-adherent or combinations thereof. [0049] In an embodiment, the excipient may be selected from lactose monohydrate, lactose, sodium saccharin, sucralose, sucrose, fructose, talc, magnesium stearate, calcium stearate, zinc stearate, stearic acid, mannitol, water, strawberry flavor, orange flavor, lemon flavor, menthol flavor, raspberry flavor, or combinations thereof. A single excipient may perform multiple roles; such as lactose monohydrate may function as a sweetener and diluent. [0050] In an embodiment, the pharmaceutically acceptable excipient may be present in a weight range of about 3.5% to about 10% w/w of the formulation. [0051] In an embodiment, the tablet may have a thickness in the range of 2.03mm to 2.38mm.
[0052] In some embodiments of the present disclosure, the ODT may further comprise additional active ingredient(s) selected from one or more of group consisting of: ace-inhibitors, anti-Alzheimer's agents, antianginal drugs, anti-

arrhythmias, anti-asthmatics, anti-cholesterolemics, analgesics, anesthetics, anti-convulsants, anti-depressants, anti-diabetic agents, anti-diarrhea preparations, antidotes, anti-emetics, anti-histamines, anti-hypertensive drugs, anti¬inflammatory agents, anti-lipid agents, anti-manics, anti-migraines, anti-nauseants, anti-stroke agents, anti-thyroid preparations, anti-tumor drugs, anti¬viral agents, acne drugs, alkaloids, amino acid preparations, anti-tussives, anti-uricemic drugs, anti-viral drugs, anabolic preparations, systemic and non-systemic anti-infective agents, anti-neoplasties, anti-parkinsonian agents, anti-rheumatic agents, anxiolytics, anti-psychotics, appetite stimulants, biological response modifiers, blood modifiers, bone metabolism regulators, bronchodilators, cardiovascular agents, central nervous system stimulates, cholinesterase inhibitors, contraceptives, decongestants, dietary supplements, dopamine receptor agonists, endometriosis management agents, enzymes, erectile dysfunction agents, fertility agents, gastrointestinal agents, H2-antagonists, homeopathic remedies, hormones, hypercalcemia and hypocalcemia management agents, immunomodulators, immunosuppressives, migraine preparations, motion sickness treatments, muscle relaxants, non-steroidal anti-inflammatories (NSAID's), obesity management agents, osteoporosis preparations, oxytocics, parasympatholytics, parasympathomimetics, prostaglandins, psychotherapeutic agents, respiratory agents, sedatives, serotonin 5-HT3 receptor antagonists, smoking cessation aids, sympatholytics, tremor preparations, urinary tract agents, vasodilators, laxatives, antacids, ion exchange resins, anti-pyretics, appetite suppressants, expectorants, anti-anxiety agents, anti-ulcer agents, anti¬inflammatory substances, coronary dilators, cerebral dilators, peripheral vasodilators, psycho-tropics, stimulants, anti-hypertensive drugs, vasoconstrictors, migraine treatments, antibiotics, tranquilizers, anti-psychotics, anti-tumor drugs, anti-coagulants, anti-thrombotic drugs, hypnotics, anti-emetics, anti-nauseants, anti-convulsants, neuromuscular drugs, hyper- and hypo-glycemic agents, thyroid and anti-thyroid preparations, diuretics, anti-spasmodics, anti-obesity drugs, erythropoietic drugs, anti-asthmatics, cough suppressants, mucolytics, DNA and genetic modifying drugs, and combinations thereof.

[0053] In some embodiments of the present disclosure, the ODT may further comprise additional hypoglycemic agent selected from, but not limited to, a PPAR Gamma agonist (peroxisome proliferator-activated receptor gamma) or Glitazone, like rosiglitazone, pioglitazone, and balaglitazone and derivatives thereof; a PPAR Gamma and Alpha agonist or Glitazar like terapglitazar, muraglitazar, and ragaglitazar and derivatives thereof; a dipeptidyl peptidase inhibitor (DPPIV); acarbose or derivative thereof; a hypocholesterol agent of fibrate type, such as fenobibrate and derivatives thereof; or combinations thereof. [0054] The starch of the present disclosure is a super-disintegrant that provides an alternative to conventional synthetic disintegrants such as sodium starch glycolate and crospovidone. When super-disintegrants are exposed to water, they swell, hydrate, change volume or shape, and create a disturbance in the tablet. Cajanus cajan starch is favored to semi-synthetic and synthetic mucilages, since it has strong swelling properties, is cost-effective, easily accessible and it is neither irritating nor toxic in nature.
[0055] The formulation rapidly disintegrates on contact with saliva of a subject. The formulation has low wetting time, disintegration time and drug release time. The formulation has an immediate-release profile, a fast onset of action, and due to its ease of swallowing has strong patient compliance. The formulation eases administration of metformin hydrochloride to elderly and/or children. [0056] The components of the formulation provide a synergistic effect with improved stability, low in vitro disintegration time, high water absorption ratio and low wetting time.
[0057] In some embodiments, the in vitro disintegration time may be less than 60 seconds. In some embodiments, the water absorption ratio may be higher than 50. In some embodiments, the wetting time may be less than 22 seconds. [0058] In an embodiment, the present disclosure provides a process of manufacturing an orodispersible tablet formulation comprising the steps of: (a) extracting Cajanus cajan starch from Cajanus cajan seeds; (b) optionally modifying the Cajanus cajan starch by microwave heating; (c) mixing the

Cajanus cajan starch with metformin hydrochloride and a pharmaceutical^
acceptable excipient; and (d) compressing to form the tablet formulation.
[0059] In an embodiment, the Cajanus cajan starch is extracted from Cajanus
cajan seeds by grinding the seeds, forming a slurry with a solvent and filtering the
slurry. The filtered slurry is left for sedimentation of the starch. The obtained
sediment is crushed and dried to give the Cajanus cajan starch. In an
embodiment, the solvent may be water or distilled water. In some embodiments,
when the modified starch becomes too dry water may be added followed by
freeze-drying to give the Cajanus cajan starch.
[0060] In an embodiment, the starch may be modified by microwave assisted
method by exposing a solution of the starch at about 70°C to about 150°C for
about 2 minutes to about 5 minutes at a power of about 800 W.
[0061] In an embodiment, the step (c) may be preceded by sizing and sieving of
the Cajanus cajan starch.
[0062] In an embodiment, the tablets may be compressed by direct compression
or granulation. Preferably the tablets are made by direct compression in a die
cavity. The compression pressure may range from about 8kN to about lOkN and
any conventional equipment for compression may be used for the purposes of the
present disclosure.
[0063] In an embodiment, the present disclosure provides a medicament
comprising the orodispersible tablet formulation.
[0064] In an embodiment, the disclosure provides use of the orodispersible tablet
formulation or the medicament for management of diabetes mellitus and
associated disorders in a subject.
[0065] In an embodiment, the present disclosure provides a method of
management of diabetes mellitus in a subject by administering to the subject an
effective amount of the orodispersible tablet formulation.
[0066] While the foregoing describes various embodiments of the disclosure,
other and further embodiments of the disclosure may be devised without departing
from the basic scope thereof. The scope of the invention is determined by the
claims that follow. The invention is not limited to the described embodiments,

versions or examples, which are included to enable a person having ordinary skill in the art to make and use the invention when combined with information and knowledge available to the person having ordinary skill in the art. EXAMPLES
[0067] The disclosure will now be illustrated with working examples, which is intended to illustrate the working of disclosure and not intended to take restrictively to imply any limitations on the scope of the present disclosure. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this disclosure belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice of the disclosed methods and compositions, the exemplary methods, devices and materials are described herein. It is to be understood that this disclosure is not limited to particular methods, and experimental conditions described, as such methods and conditions may vary. [0068] MATERIALS: Metformin hydrochloride was obtained from Yarrow Chem. Pvt. Ltd., Mumbai. Sodium starch glycolate, lactose monohydrate, magnesium stearate, talc and sodium saccharin were procured from Loba Chemie Pvt. Ltd., Mumbai. Cajanus cajan seeds were purchased from a local vendor in Rajpura, Punjab. All the chemicals and reagents were of analytical grade. EXAMPLE 1: PREPARATION OF CAJANUS CAJAN STARCH [0069] Cajanus cajan (pigeon pea) seeds were washed several times with water before being ground into a fine paste in a laboratory blender. The paste was dissolved in water to give a slurry and the slurry was strained through a fine muslin cloth and the filtrate was permitted to settle. After 12-hour interval, the supernatant was discarded and the starch sediment was treated with distilled water. The starch sediment was spread out on trays and heated for two days at 60°C in a hot air oven. Mortar-pestle and laboratory blender were used to crush the dried mass and a 60 mm sieve was used to sieve the fine powder. The attained starch was white to off white in color and was weighed and kept in an airtight container. The yield of the Cajanus cajan starch obtained was calculated to be 32.4% and was calculated using the following formula:

Weiqht of starch after dryinq
Yield (%) = ..; . ht f ' —^-X 100
Weight of seeds
[0070] Modification of Cajanus cajan starch: The extracted starch sample was put in distilled water (20 percent w/v) for 24 hours at room temperature to give a suspension. The starch suspension was modified in the microwave by heating it for 3 minutes in the microwave. Since the microwave modification dried up the samples, an equivalent amount of water was applied to remove the residue from the treated sample. Starch powder was obtained for further analysis by freeze drying the starch.
EXAMPLE 2: CHARACTERIZATION OF THE MICROWAVE MODIFIED STARCH
2.1 Phytochemical tests for microwave modified Cajanus cajan starch: [0071] Several phytochemical tests such as Biuret's test, Mayer's test and Molisch's test were performed for the identification of alkaloids, carbohydrates, glycosides, proteins and steroids. The results for the above mentioned tests have been provided in Table No. 1.
2.2 Gelation temperature:
[0072] The starch powders were moistened with water and moved into capillary tubes to determine the gelation temperature. A melting point apparatus was used to monitor the temperature of gelling and the time from swelling to complete gelation. The results for the above mentioned tests have been provided in Table No. 1.
2.3 Determination of pH:
[0073] A digital pH meter was used to assess the pH of 1 % starch suspension in water. The pH was close to neutral.
2.4 Viscosity:
[0074] Brookfield viscometer was used to determine the viscosity of 1% starch suspension. The viscosity obtained has been provided in Table No. 1.
2.5 Water Absorption index:

[0075] The starch sample was suspended in 10 mL distilled water at 30 °C in a
centrifuge tube, stirred for 30 minutes, and centrifuged at 3000 rpm for the next
10 minutes to determine the water absorption index. The gel formed was weighed
after the supernatant was decanted. The gel weight per gram of dry sample was
then used to measure the water absorption index and the result has been provided
in Table No. 1. The significantly high water absorption index observed for the
Cajanus cajan starch was related to the disintegration mechanism which acts by
swelling on contact with aqueous medium.
Bound water (g)
Water absorption index (%) = „,, , 7 :—-r^-X100
Weight sample (g)
Table No. 1: Characteristics of microwave modified Cajanus cajan starch

Parameter (unit) Results for Cajanus cajan starch
Test for carbohydrates Barfoed's test +
Benedict's test +
Molisch'stest +
Test for polysaccharides Iodine test +
Test for proteins Biuret's test +
Test for alkaloids Mayer's test +
Test for glycosides Keller-Killani test +
Test for steroids Liebermann-Burchard test +
Salkowiesk test +
Test for flavanoids Ferric Chloride -
Lead acetate test -
Test for saponins Foam test -
Gelation temperature (°C) 75
Gelling time (mins) 15-20

pH 6.9
Viscosity (cP) 593
Water absorption index (%>) 102.88
EXAMPLE 3: Orodispersible Tablet Formulations (ODFs)
[0076] Metformin hydrochloride ODFs were prepared with modified Cajanus cajan starch at different concentrations of 5%, 7.5%, 10%, and 15% w/w of modified Cajanus cajan starch (ODF 2 to ODF 5) applying direct compression. For comparison, ODFs were prepared without using any disintegrant (ODF 1) and using sodium starch glycolate as disintegrant (ODF 6 to ODF 9) at the same concentrations as Cajanus cajan starch. The ingredients were all filtered through a 60 mesh sieve. A powder blend was prepared with the starch and metformin hydrochloride as per the formulation of Table No. 2. The powder blend was uniformly blended and compressed into 550 mg tablets using 8-mm round flat punches on a rotary punching machine using a weighted quantity of each ingredient.
Table No. 2. Oro-dispersible Tablet Formulations

Ingredient Formulation

ODF
1 ODF
2 ODF
3 ODF
4 ODF
5 ODF
6 ODF
7 ODF
8 ODF
9
Metformin HC1 500 500 500 500 500 500 500 500 500
Cajanus cajan Starch — 10 15 20 30 — — — —
Sodium
starch
glycolate — — — — — 10 15 20 30
Lactose
monohydra
te 45 35 30 25 15 45 30 25 15
Sodium saccharin 1 1 1 1 1 1 1 1 1
Talc 2 2 2 2 2 2 2 2 2
Magnesiu m stearate 2 2 2 2 2 2 2 2 2

Total
Weight
(mg) 550 550 550 550 550 550 550 550 550
[0077] A FTIR spectrum was run for metformin hydrochloride without (Figure 1) and with the modified Cajanus cajan starch (Figure 2). The key peak in the spectrum of the pure drug metformin hydrochloride does not vary substantially from that with the modified starch. The characteristic absorption stretch for 1688.48cm"1 was observed in the FTIR spectra of pure metformin hydrochloride, suggesting the presence of the C=N (stretch) functional group. A plateau can be seen at 1254.14 cm"1, showing the presence of C-N stretching. A peak is also visible at 1473.34 cm"1, showing the presence of C-H (bend in plane). A peak at 732.97 cm"1, on the other hand, suggests the existence of the N-H (rocking) functional group. All other peaks were located in the FT-IR spectra's finger print area. The substantial similarity of the spectra demonstrates that the drug is compatible with the microwave modified Cajanus cajan starch used in the formulations.
3.1 CHARACTERIZATION OF THE POWDER BLEND BEFORE COMPRESSION
3.1.1 Angle of repose
[0078] Angle of repose values for the formulations ranged from 24.7 to 35
indicating good flow. The fixed funnel method was used to measure the angle of
repose (6), which was determined using the following equation:
height of powder cone
6 = tan ( )
radius of powder cone
3.1.2 Determination of bulk and tapped densities:
[0079] The following formula were used to measure bulk density and tapped
density:
Weight of the powder
Bulk density = -— -
bulk volume

Tapped density =
Weight of the powder
tapped volume 3.1.3 Compressibility index and Hausner's ratio:
[0080] The compressibility index and the Hausner's ratio have become common methods for predicting powder flow characteristics because they are clear, convenient, and easy to use. Both the bulk density and tapped density of granules were calculated to assess the compressibility index and Hausner's ratio. The results are presented in Table No. 3.

Compressibility index =
Hausner's ratio =
Tapped density — Bulk density
Tapped density
Tapped density
Bulk density

X100

Table No. 3: Pre-compressional parameters for powder blend of the
formulation

Formulation
sio ODF1 ODF2 ODF3 ODF ODF ODF ODF ODF ODF
4 5 6 7 8 9
ter
sf 35±10. 27.3±0.2 25.9±0. 26±0. 24.7± 29.2± 28.8± 28.5± 27.8±
9) 1 2 5 0.9 0.3 0.3 0.2 0.1
0.65±0. 0.48±0.0 0.47±0. 0.47± 0.45± 0.48± 0.48± 0.46± 0.47±
f ) 05 2 04 0.02 0.03 0.02 0.02 0.03 0.02
i 0.81±0. 0.60±0.0 0.63±0. 0.62± 0.64± 0.54± 0.55± 0.53± 0.56±
y ) 03 1 02 0.05 0.31 0.03 0.04 0.02 0.05
sib 21±0.0 12.95±1. 13.68± 14.63 15.23 13.83 14.08 14.23 14.94
ex 4 20 1.43 ±1.60 ±0.53 ±1.47 ±1.35 ±1.29 ±1.25
-'s 1.35±0. 1.27±0.0 1.23±0. 1.19± 1.15± 1.48± 1.41± 1.34± 1.28±

03 26 052 0.031 0.025 0.041 0.036 0.031 0.028
3.2 CHARACTERIZATION OF THE TABLET
Post-compressional parameters were determined for the orodispersible tablets formed by the above formulations.
3.2.1 Tablet hardness:
[0081] The Monsanto hardness tester was used to assess hardness, which was expressed in kg/cm2.
3.2.2 Tablet thickness:
[0082] Vernier callipers scale was used to measure the thickness of the tablets. Five measurements were taken.
3.2.3 Weight variation:
[0083] Each formulated batch had 20 tablets, chosen at random and weighed individually. For the weight difference, the individual weights were compared to the average weight.
3.2.4 Friability:
[0084] Five tablets were measured and put in a Roche friabilizer of the USP form. The friability was measured at 25 rpm, or 100 revolutions per minute, for 4 minutes. The tablets were then dusted and measured again. There should be no more than a 1% weight loss. The following formula was used to measure the
percentage weight loss (reliability):
Initial weight of the tablet — Final weight of the tablet
Friability = — — X100
Initial weight of the tablet
3.2.5 Drug content uniformity
[0085] Ten tablets were randomly weighed and crushed to fine powder, and a quantity of powder equivalent to 50 mg of metformin hydrochloride was put in a 100 ml of volumetric flask and diluted with methanol. Then the solution was filtered finally made up to 100 mL using pH 6.8 phosphate buffer. A UV-Visible spectrometer was used to determine the content of metformin hydrochloride by measuring the absorbance at 240 nm. The standard calibration curve was used to assess the drug quality.

3.2.6 Wetting time:
[0086] Wetting time is an important parameter. It helps in studying the effect of
different excipients in the disintegration of the tablet. A piece of tissue paper
folded twice was placed in a small Petri dish containing 6 ml of pH 6.8 phosphate
buffer and one millilitre of water containing amaranth (water soluble dye) was
added, a tablet was put on the paper, and the time for complete wetting was
measured.
3.2.7: Water absorption ratio:
[0087] The weight of the tablet was measured before it was put in the Petri dish
(Wb). A completely wetted tablet was extracted from the Petri dish and reweighed
(Wa). The following equation was used to measure the water absorption ratio (R):
Wa-Wb
R=—TTTT—*100 Wb
where, Wb and Wa denote the tablet weights before and after water absorption respectively.
3.2.8 In vitro disintegration time:
[0088] Disintegration is a method of breaking down a tablet into smaller particles. The formulation's in vitro disintegration period was calculated using a US Pharmacopoeia monograph for tablet disintegration research. The disintegration period was described as the amount of time needed for quick disintegration formulations to fully disintegrate until no solid residue is left. As the immersion liquid, phosphate buffer pH 6.8 (simulated saliva fluid) was held at 37°±2°C. A thermometer was used to continuously track the temperature of the medium and the disintegration time was recorded to the second using a digital stopwatch. To ensure optimum precision, only one tablet was examined at a time. Tablet excipients and water were removed by washing and drying. From each batch 6 tablets were tested, and the results are stated as mean standard deviation. The tablet's in-vitro disintegration period was measured according to IP specifications using a disintegration test apparatus.

0DF7 0DF6 0DF5 0DF4 0DF3 ODF2 ODF1 Formulation
2.13±0.02 2.03±0.01 2.32±0.03 2.38±0.08 2.33±0.05 2.18±0.03 2±0.02 Thickness (mm)
2.8±0.22 3±0.12 3.5±0.11 2.9±0.14 3.4±0.17 3.2±0.18 4.4±0.20 Hardness (kg/cm2)
0.5±0.01 0.6±0.02 0.5±0.03 0.5±0.03 0.5±0.01 0.5±0.01 0.6±0.03 Friability (%)
559.2±1.21 242.5±1.13 552.7±1.50 547.3±1.46 552.2±0.14 556.1±0.55 554.1±0.51 Weight Variation (mg)
94.23±0.54 94.18±0.53 95.69±0.5 94.98±0.51 94.38±0.54 94.24±0.54 94.13±0.55 Drug Content Uniformity
127.6±0.21 141.3±0.32 53.3±0.57 92.5±0.68 114.2±0.39 137.1±0.24 187.2±0.14 In vitro Dis-integration Time (s)
48.24 52.31 22.21 26.47 29.04 32.39 300.24 Wetting Time
00
45.52 43.16 52.57 51.92 51.22 50.73 12.02 Water
absorption
Ratio

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o
n
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n
VI VI
O* S
o s?
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% re n
o
a
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ST
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0DF8 2.18±0.04 3.1±0.18 0.6±0.03 554.4±1.52 94.88±0.51 97.1±0.28 45.78 46.42
0DF9 2.25±0.05 3.3±0.18 0.5±0.04 558.4±1.44 95.73±0.5 72.3±0.58 34.52 49.27
3.2.9 In vitro drug release profile:
[0089] The ability to analyze the quality of formulations using dissolution has emerged as a simple, fast, and sensitive process. According to BCS scientific principles it is noticed that as a result of different drug dissolution, in-vivo variations in the rate and degree of absorption of a drug from two pharmaceutically equivalent solid oral products occur. Material properties, formulation variables, and storage influence the rate of dissolution of immediate release dosage types. Thus, sensitive and repeatable dissolution data derived from physiologically, chemically, and hydrodynamically specified parameters can be used as a surrogate for in-vitro bioavailability. In vitro drug release studies of various formulation was carried out in 900mL of phosphate buffer (pH 6.8) at 37±0.5 °C with the stirrer rotation speed of 50 rpm using USP dissolution apparatus using a paddle stirrer (Type II). A 5mL aliquot of dissolution medium was withdrawn at 5, 10, 15, 20, 25, 30, 35, 40, 45, and 50 minutes and replaced with same amount of buffer with help of pipette. The samples were assayed spectrophotometrically at 234 nm. Table No. 5 provides the results for in vitro drug release profile of the formulation. Figure 3 provides graphically the in vitro cumulative %drug release profiles of orodispersible tablet formulations, ODF1 to ODF9, as per an embodiment of the present disclosure.

Table No. 5: In vitro drug release profiles for the oral dispersible
formulations

Time(min ODF1 ODF2 ODF3 ODF4 ODF5 ODF6 ODF7 ODF8 ODF9
o o o o o o o o o o
T) 5.16 32.12 35.48 39.18 41.77 29.11 31.54 34.29 39.78
o 8.48 45.36 46.74 46.88 50.17 38.51 41.85 49.15 50.04
T) 11.55 52.84 52.95 55.21 62.41 45.19 49.47 52.88 58.28
o 17.58 67.19 70.01 69.22 73.19 53.79 56.84 62.5 67.42
CN 23.44 71.11 74.11 77.18 80.54 64.76 68.73 71.8 74.36
O CO 28.79 71.38 75.21 79.44 91.25 71.54 73.59 77.22 81.25
CO 33.08 71.4 75.39 80.01 91.42 73.42 73.87 78.14 81.51
o 37.61 71.42 75.54 80.16 92.51 73.42 73.87 78.21 83.84

VO (N ^r VO (N t-~ ^r
T) <—' ^r ir> < ' T) ^r 00 (N 00
*T 00 ,—i T) o CN ro m 00 m
eo t-~ t-~ 00 ON t-~ t-~ t-~ 00
(N ^r VO (N t-~ ^r
O < ' ^r ir> < ' >/"> ^r 00 (N 00
i/~> o ,—i T) o (N ro m 00 CO
^r t-~ t-~ 00 ON t-~ t-~ t-~ 00
INFERENCE
[0090] As mechanical integrity is essential in the formulation of oral disintegrating tablets, for the formulations 0DF2 to 0DF9, the hardness was calculated and preserved between 2.8 kg/cm3 and 3.5 kg/cm3. Since quick disintegrating tablets are not as hard as the standard tablets, because of the lower compression used, they can be brittle and require individual packaging. It was noticed that all of the formulations were almost uniform in hardness in the particular process and had strong mechanical strength and hardness, from the low standard deviation values. The tablets had a pharmaceutical content ranging from 94.13±0.5 mg to 95.73±0.55 mg. This suggested that the medication quality was clear in all formulations.
[0091] The inner configuration of tablets is closely linked to wetting. The wetting time and water absorption ratio are essential measures of a disintegrant's tendency to swell in the presence of a small volume of water. The tablets containing sodium starch glycolate (ODF6 to ODF9) had a wetting time in the range of 72.3 to 141.3 sees, while the tablets containing different concentrations of microwave modified Cajanus cajan starch (ODF2-ODF5), had wetting time in the range from 32.39 to 22.21 sees. The wetting time is inversely proportional to the concentration of super-disintegrant, it is decreased as the concentration of super-disintegrant is increased, and is directly proportional to the disintegration time of the formulation in the oral cavity, as it is increased as the wetting time is increased (Table No. 4). The water absorption ratio values of formulations with microwave modified Cajanus cajan extract, ODF2-ODF5, were found to be in the range of 50.73 to 52.57 and water absorption ratio of the formulations with sodium starch

glycolate, ODF6-ODF9, were in the range of 43.12 to 49.27. This indicated that the water absorption ratio of the microwave modified Cajanus cajan was better than sodium starch glycolate.
[0092] When opposed to formulations with sodium starch glycolate, the in vitro drug release rate from formulations with microwave modified Cajanus cajan was found to be faster. The composition of the disintegrant, which causes the tablet to split up into smaller fragments as it comes into contact with physiological fluid, is linked to the disintegration period, which is influenced by the tablet's hardness. The in vitro disintegration time of formulations containing microwave modified Cajanus cajan (ODF2-ODF5) was in the range from 137.1 ± 0.24 sec to 53.3 ± 0.57 sec.
3.3 DRUG RELEASE KINETICS AND STABILITY OF FORMULATION [0093] In vitro release data of metformin hydrochloride orodispersible tablets was fitted into zero order, first order, Higuchi, Korsmeyer Peppas and Hixon Crowell release models to find the perfect release model which best describes the mechanism of the drug release. It was found that the drug released by first-order kinetics, which was indicated by the maximum R2 value 0.952. Table No. 6 provides the statistical results for ODF5. Table No. 6. Drug release Kinetics of Model Fitting in Optimized Metformin
hydrochloride Oro-dispersible tablets

Model R2 Slope Intercept
Zero Order 0.7885 7.8965 22.465
First Order 0.952 0.121 2.0325
Higuchi 0.9183 0.6166 0.8679
Hixon-Crowell 0.907 0.271 4.4631
Korsmeyer-peppas 0.8535 1.1745 44.53
[0094] Stability studies of optimized formulation (ODF5) carried out for one month are provided in Table No. 7.

Table No. 7: Stability Studies of Optimized Formulation (ODF5)

Specification Initial 15 Days 30 Days
Average weight (mg) 552.7 552.3 552.1
Hardness (kg/cm2) 3.5 3.5 3.2
Drug Content(%) 95.69 95.33 95.18
Disintegration time (sec) 53.3 53.7 54.2
[0095] Based on the above examples, Cajanus cajan starch can be used as a super-disintegrant in the formulation of orodispersible tablets of metformin hydrochloride.
[0096] From the foregoing, it will be appreciated that, although specific embodiments of the invention have been described herein merely for purposes of illustration, various modifications may be made without deviating from the spirit and scope of the invention and should not be construed so as to limit the scope of the invention or the appended claims in any way.
ADVANTAGES OF THE PRESENT INVENTION
[0097] The present disclosure provides an orodispersible tablet formulation of
metformin hydrochloride that has patient compliance, fast onset of action, low
side effects, and good stability.
[0098] The present disclosure provides an orodispersible tablet formulation
comprising natural super-disintegrant that is economic, non-toxic, stable, and easy
to produce.
[0099] The present disclosure provides an orodispersible tablet formulation that
has low in vitro disintegration time, high water absorption ratio and low wetting
time.

We Claim:

1. An orodispersible tablet formulation comprising metformin hydrochloride and Cajanus cajan starch.
2. The formulation as claimed in claim 1, wherein the formulation comprises metformin hydrochloride in a weight range of 85% to 90% w/w with respect to the formulation.
3. The formulation as claimed in claim 1, wherein the formulation comprises Cajanus cajan starch in a weight range of 1.5% to 6% w/w with respect to the formulation.
4. The formulation as claimed in claim 1, wherein the Cajanus cajan starch is obtained from Cajanus cajan seeds.
5. The formulation as claimed in claim 1, wherein the Cajanus cajan starch is microwave modified starch.
6. The formulation as claimed in claim 5, wherein the microwave modified starch is starch modified by microwave assisted method by exposing a solution of the starch at 70°C to 150°C for 2 minutes to 5 minutes at a power of 800 W.
7. The formulation as claimed in claim 1, wherein the formulation further comprises a pharmaceutically acceptable excipient.
8. The formulation as claimed in claim 7, wherein the excipient is selected from lactose monohydrate, lactose, sodium saccharin, sucralose, sucrose, fructose, talc, magnesium stearate, calcium stearate, zinc stearate, stearic

acid, mannitol, water, strawberry flavor, orange flavor, lemon flavor, menthol flavor, raspberry flavor, or combinations thereof.
9. The formulation as claimed in claim 7, wherein the excipient is present in a weight range of 3.5% to 10% w/w of the formulation.
10. A process of manufacturing an orodispersible tablet formulation comprising the steps of: (a) extracting Cajanus cajan starch from Cajanus cajan seeds; (b) optionally modifying the Cajanus cajan starch by microwave heating; (c) mixing the Cajanus cajan starch with metformin hydrochloride and a pharmaceutically acceptable excipient; and (d) compressing to form the tablet formulation.