[0001] The present disclosure relates generally to the field of pharmaceuticals. Specifically, the disclosure is directed to a pharmaceutical formulation for immediate release comprising solid dispersions of anti-hypertensive drug- Valsartan and ß-cyclodextrin along with mucilage of Hibiscus rosasinensis or China rose.

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] Oral drug delivery is the simplest and easiest way of administering drugs. Due to greater solubility, smaller bulk, accurate dosage and easy production, solid dosage forms have many advantages over other types of oral dosage forms. Most of the NCEs (New Chemical Entity) under development these days are intended to be used as solid dosage forms that originate on effective reproducible in vivo plasma concentration after oral administration. One of the key properties required for successful development of pharmaceutical dosage forms is adequate aqueous solubility of the new chemical entities. Nearly 40 % of NCEs currently being discovered are poorly water-soluble. Poorly water-soluble drugs have the limitation of slower absorption, leading to unpredictable, inadequate and variable bioequivalence ( Ketan T. Savjani, Anuradha K. Gajjar, and Jignasa K. Savjani. “Drug Solubility:Importance and Enhancement Techniques.”, International Scholarly Research Network ISRN Pharmaceutics Volume 2012). Poorly soluble drugs often require higher doses in order to reach therapeutic plasma concentration after oral administration.
[0004] Solid dispersions of poorly water-soluble drugs with water-soluble carriers have reduced the incidence of these problems by enhancing dissolution. The development of solid dispersions as a practically viable method to enhance bioavailability of poorly water-soluble drugs overcame the limitations of previous approaches such as salt formation, solubilization by co-solvents, and particle size reduction. The drug is molecularly dispersed in the matrix, thereby forming a solid dispersion. When the solid dispersion is exposed to aqueous media, the carrier dissolves and the drug releases as fine colloidal particles. However, solid dispersions may not always be easy to achieve. The physical state of solid dispersion will depend on the physicochemical properties of the carrier and the drug, the drug-carrier interactions and the preparation methods.
[0005] Valsartan is a non peptide, orally active, and specific angiotensin II receptor blocker acting on the AT1 receptor subtype. It is a white powder, relatively insoluble in water. It belongs to BCS class II category which means it has low solubility and high permeability. Owing to its low solubility there is a need in the art to develop solid dispersions that enhance its bio-availability. Further, the bioavailability of drug is dependent on in vivo disintegration, dissolution, and various physiological factors which depend on the formulation prepared with the solid dispersions. In recent years, scientists have focused their attention on formulations for quick disintegration, as they are preferred by pediatric and geriatric patients increasing patient compliance. Moreover, the drug dissolution is facilitated by the tablet’s quick disintegration.
[0006] There is a need in the art to develop formulations that give improved drug release, dissolution and bio-availability of Valsartan along with better physical characteristics.

OBJECTS OF THE INVENTION
[0007] An object of the present disclosure is to provide a pharmaceutical formulation of Valsartan that has improved release profile.
[0008] An object of the present disclosure is to provide a pharmaceutical formulation for immediate release of Valsartan.
[0009] An object of the present disclosure is to provide a pharmaceutical formulation of Valsartan which is stable, easy to administer and safe.
[0010] An object of the present disclosure is to provide a process of preparation of a pharmaceutical formulation for immediate release of Valsartan.
SUMMARY OF THE INVENTION
[0011] 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.
[0012] In an aspect, the present disclosure provides a pharmaceutical formulation for immediate release comprising:
(a) solid dispersions comprising Valsartan or pharmaceutically acceptable salts thereof and ß-cyclodextrin;
(b) mucilage of Hibiscus rosasinensis or China rose; and
(c) at least one pharmaceutically acceptable excipient;
wherein the weight ratio of Valsartan to ß-cyclodextrin is 1:2.5; and
wherein the weight ratio of the mucilage of Hibiscus rosasinensis to the solid dispersions is in the range of 1:8 to 1:10.
[0013] In an aspect, the present disclosure provides a process of preparing a pharmaceutical formulation comprising the steps of:
(a) boiling and concentrating powder of Hibiscus rosasinensis in water and thereafter precipitating with acetone to extract mucilage of Hibiscus rosasinensis;
(b) preparing a solid dispersion of Valsartan or pharmaceutically acceptable salts thereof and ß-cyclodextrin by freeze drying; and
(c) mixing mucilage of Hibiscus rosasinensis and at least one pharmaceutically acceptable excipient with the solid dispersion to obtain the pharmaceutical formulation;
wherein the weight ratio of Valsartan to ß-cyclodextrin is 1:2.5; and
wherein the weight ratio of the mucilage of Hibiscus rosasinensis to the solid dispersions is in the range of 1:8 to 1:10.
[0014] In an aspect, the present disclosure relates to a method of treating a subject by administering a pharmaceutically effective amount of the formulation.
[0015] In an aspect, the present disclosure relates to use of the pharmaceutical formulation for the treatment, amelioration or prevention of cardiovascular, renal or associated conditions in a subject.
[0016] 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
[0017] 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.
[0018] Figure 1 depicts equilibrium solubility of the drug in different solid dispersions as per an embodiment of the present invention.
[0019] Figure 2 shows FTIR spectrum of pure drug (Valsartan).
[0020] Figure 3 shows FTIR spectrum of ß-cyclodextrin.
[0021] Figure 4 shows FTIR spectrum of solid dispersion 4 as per an embodiment of the present invention.
[0022] Figure 5 shows DSC thermogram of pure drug (Valsartan).
[0023] Figure 6 shows DSC thermogram of ß-cyclodextrin
[0024] Figure 7 shows DSC thermogram of solid dispersion 4 as per an embodiment of the present invention.
[0025] Figure 8 depicts the Scanning Electron Micrograph of the drug at 1000x(a) and 2000x(b).
[0026] Figure 9 depicts Scanning Electron Micrograph of ß-cyclodextrin at 1000x(a) and 2000x(b).
[0027] Figure 10 depicts Scanning Electron Micrograph of solid dispersion 4 as per an embodiment of the present invention at 1000x (a) and 2000x (b).
[0028] Figure 11 shows X-RD of the drug (Valsartan).
[0029] Figure 12 shows X-RD of the ß-cyclodextrin.
[0030] Figure 13 shows X-RD of the Solid Dispersion 4 as per an embodiment of the present invention.
[0031] Figure 14 displays in vitro drug release profile of various solid dispersions as per an embodiment of the present invention and pure drug.
[0032] Figure 15 displays comparative in vitro drug release profiles of various formulations of immediate release tablets as per an embodiment of the present invention and marketed product (Valent).
[0033] Figure 16 plots the Zero Order Model for drug release profile of Optimized Immediate Release formulation (F1) as per an embodiment of the present invention.
[0034] Figure 17 plots the First Order Model for drug release profile of Optimized Immediate Release formulation (F1) as per an embodiment of the present invention.
[0035] Figure 18 plots the Higuchi Release model for drug release profile of Optimized Immediate Release formulation (F1) as per an embodiment of the present invention.
[0036] Figure 19 plots the Hixon-Cowel Release model for drug release profile of Optimized Immediate Release formulation (F1) as per an embodiment of the present invention.
[0037] Figure 20 plots the Koresmeyere Peppas model for drug release profile of Optimized Immediate Release formulation (F1) as per an embodiment of the present invention.

DETAILED DESCRIPTION OF THE INVENTION
[0038] 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.
[0039] 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.
[0040] 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.
[0041] In some embodiments, numbers have been used for quantifying weights, 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.
[0042] 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.
[0043] 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.
[0044] 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.”
[0045] 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.
[0046] 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.
[0047] 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.
[0048] 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.
[0049] 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.
[0050] The headings and abstract of the invention provided herein are for convenience only and do not interpret the scope or meaning of the embodiments.
[0051] 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.
[0052] The term, "pharmaceutically acceptable" as used herein refers to a carrier comprised of a material that is not biologically or otherwise undesirable.
[0053] 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.
[0054] The present disclosure relates to the hypertension drug-Valsartan. Valsartan belongs to the category of Angiotensin II blocker, used in the treatment of hypertension, heart failure and reduction of cardiovascular mortality in clinically stable patients with left ventricular failure or left ventricular dysfunction following myocardial infarction. It is poorly soluble in water and has an oral bioavailability of ~23% to 25%.
[0055] In an embodiment, the present disclosure provides a pharmaceutical formulation for immediate release comprising:
(a) solid dispersions comprising Valsartan or pharmaceutically acceptable salts thereof and ß-cyclodextrin;
(b) mucilage of Hibiscus rosasinensis or China rose; and
(c) at least one pharmaceutically acceptable excipient;
wherein the weight ratio of Valsartan to ß-cyclodextrin is 1:2.5; and
wherein the weight ratio of the mucilage of Hibiscus rosasinensis to the solid dispersions is in the range of 1:8 to 1:10.
[0056] In a preferred embodiment, the weight ratio of the mucilage of Hibiscus rosasinensis to the solid dispersions may be 1:9.
[0057] In an embodiment, the mucilage of Hibiscus rosasinensis may be obtained from the leaves of Hibiscus rosasinensis.
[0058] In an embodiment, the pharmaceutically acceptable excipient may be selected from those generally known in the art, including but not limited to, binders, glidants, lubricant, coloring agents, flavoring agents, diluents, bulking agent, stabilizers, emulsifiers, sweeteners and combinations thereof. The excipient must be compatible with the active pharmaceutical ingredient.
[0059] In an embodiment, the pharmaceutically acceptable excipient may be selected from lactose, dextrin, maltodextrin, glucose, sorbitol, sucrose, mannitol, colloidal silica, silicates, stearate salts like magnesium stearate, calcium stearate, sodium chloride, starch, cellulose, methylcellulose, hydroxyl propylcellulose, hydroxypropyl methylcellulose, cellulose acetate, sodium saccharin, acacia gum, polyvinyl pyrrollidone (PVP), microcrystalline cellulose (MCC), titanium oxide, guar gum, polyethylene glycol, talc and combinations thereof.
[0060] In an embodiment, the pharmaceutical formulation may be administered in a solid dosage form.
[0061] In an embodiment, the pharmaceutical formulation may be administered in a solid dosage form, including tablets, pellets, powders, capsules, lozenges, pills, granules, and sachets. Preferably, the pharmaceutical formulation may be administered in the form of a tablet.
[0062] In an embodiment, the formulation may also be prepared in the form of a liquid or semi-solid, including suspensions, emulsions, creams, gels, pastes, suppositories and the like.
[0063] In an embodiment, the pharmaceutically acceptable salts include those that possess the same or better activity than Valsartan, including sodium salt, potassium salt, calcium salt, disodium salt, dipotassium salt, magnesium salt, and mixtures thereof, or their hydrates or polymorphous forms.
[0064] Immediate release formulations show increased stability and solubility of the drug, allow higher drug load and higher bio-availability. The drawback of taking multiple doses of ordinary formulations to meet the desired bio-availability, is overcome by the present invention by providing better bio-availability thus making the immediate release formulation cost effective.
[0065] In an embodiment, the solid dispersions of Valsartan and ß-cyclodextrin show improved equilibrium drug solubility in comparison to pure drug. The drug solubility of the solid dispersions in phosphate buffer at pH 6.8 ranges from about 500µg/ml to about 3000µg/ml, preferably about 1000µg/ml to about 2000µg/ml.
[0066] In an embodiment, the solid dispersions do not lead to any change in the nature of the drug and maintain content uniformity.
[0067] In an embodiment, the solid dispersions show improved dissolution compared to the pure drug. Preferably, solid dispersions of Valsartan and ß-cyclodextrin show up to ~94% drug release in 30 minutes time in a phosphate buffer of pH 6.8, as opposed to 24% release in pure drug. Drug release of up to ~99% may be obtained within 60 minutes.
[0068] In an embodiment, the solid dispersion of Valsartan and ß-cyclodextrin shows an improved drug release profile at the ratio of 1:2.5 of up to ~94% release at 30 minutes. This profile is better than the release profiles at other ratios of 1:1, 1:1.5, 1:2, and 1:3, corresponding to release of ~50%, ~73%, ~81% and ~89% drug respectively, at 30 minutes.
[0069] In an embodiment, the pharmaceutical formulation comprising mucilage of Hibiscus rosasinensis has better release profile of Valsartan than other disintegrants known in the art.
[0070] In an embodiment, the pharmaceutical formulation displays immediate release such that majority of the therapeutic compound may be rapidly released, about 60%, about 70%, about 80%, about 90%, about 95%, or above 95%. The release may take place over a short time, within 1 hour, 45 minutes, 30 minutes, or 20 minutes after consumption. Preferably, over 98% of the Valsartan may be released in less than 30 minutes.
[0071] In a preferred embodiment, the pharmaceutical formulation may show up to about 99.7% release of the drug in about an hour. This is much higher than pure drug (~62%) and drug in formulation with disintegrants other than mucilage of Hibiscus rosasinensis. Hibiscus rosasinensis Linn is a natural polymer and the use of natural carrier for the preparation of immediate release tablets results in low cost, better bio-compatibility and biodegradability.
[0072] In an embodiment, the formulation possesses acceptable physicochemical characteristics - in vitro disintegration, % friability, hardness, thickness, wetting time, drug content uniformity, weight variation, water absorption ratio, ease of administration and safety.
[0073] In an embodiment, the release of Valsartan from the formulation may follow the Higuchi kinetics model.
[0074] In an embodiment, the pharmaceutical formulation may not show any significant change in average weight, hardness, drug content or disintegration over time. This indicates the formulation is stable.
[0075] In a preferred embodiment, the pharmaceutical formulation may be administered such that the weight of the solid dispersion (of Valsartan and ß-cyclodextrin) may be about 140 mg to about 15 mg of the mucilage of Hibiscus rosasinensis. The ratio of the weights of Valsartan and ß-cyclodextrin in the solid dispersions may be about 1:2.5.
[0076] In an embodiment, the present disclosure provides a process of preparing a pharmaceutical formulation comprising the steps of:
(a) boiling and concentrating powder of Hibiscus rosasinensis in water and thereafter precipitating with acetone to extract mucilage of Hibiscus rosasinensis;
(b) preparing a solid dispersion of Valsartan or pharmaceutically acceptable salts thereof and ß-cyclodextrin by freeze drying; and
(c) mixing mucilage of Hibiscus rosasinensis and at least one pharmaceutically acceptable excipient with the solid dispersion to obtain the pharmaceutical formulation;
wherein the weight ratio of Valsartan to ß-cyclodextrin is 1:2.5; and
wherein the weight ratio of the mucilage of Hibiscus rosasinensis to the solid dispersions is in the range of 1:8 to 1:10.
[0077] In an embodiment, freeze drying technique used for the formation of solid dispersions may result in porous and fluffy product that increases the surface area and in turn the surface free energy, resulting in higher solubility and dissolution of drug.
[0078] In an embodiment, the pharmaceutical formulation may be prepared in the form of a tablet by direct compression. In direct compression the blend of the components is directly compressed in a mould to form a tablet, without altering any physical characteristics of the components. Alternatively, the formulation may be prepared via dry granulation, wet granulation or other well known techniques of tablet formation.
[0079] In an embodiment, the present disclosure relates to a method of treating a subject by administering a pharmaceutically effective amount of the formulation. Pharmaceutically effective amount refers to the amount of the formulation that brings the desired therapeutic effect without overdosing. The dosage regimen may be adjusted based on the time, individual requirements, duration of treatment and medical history.
[0080] In an embodiment, the formulation may be administered for the treatment, amelioration, or prevention of hypertension, heart failure, angina, myocardial infarction, left or right ventricular dysfunction, arrhythmia, renal insufficiency, arteriosclerosis and other related disorders.
[0081] In an embodiment, the present disclosure relates to use of the pharmaceutical formulation for the treatment, amelioration or prevention of cardiovascular, renal or associated conditions in a subject.
[0082] 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.
[0083] 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.
MATERIALS
[0084] The pure Valsartan was kindly gifted by Jubilant Generics, Noida and ß-cyclodextrin was purchased from Yarrow Chem Products, Mumbai. China rose extract was extracted from Hibiscus rosasinensis in the lab. Locust bean gum was the gift sample from Lucid Colloids Ltd, Mumbai. Pregelatinized starch, crospovidone (CP) and sodium starch glycolate (SSG) were gift samples from Maple Biotech Pvt. Ltd, Pune.
The plant material has been identified and authenticated by Department of Botany, Sri Venkateswara University Tirupati – 517 502, A.P., India under reference/ Voucher number SVU/SC/45/231/18-19 as per standard protocol for identification of plants for phytochemical investigation research work.
EXAMPLE 1: PRELIMINARY STUDIES
Identification of drug and polymer:
1.1 Polymer
a) Melting Point: Melting point of the drug was determined by using melting point apparatus.
b) Determination of ?max of Valsartan using U.V Spectrophotometer: Valsartan solution was prepared in pH 6.8 phosphate buffer. ?max was determined by scanning between 200-400 nm using U.V Visible spectrophotometer. The scanned graph was according to reported literature and hence confirmed that the obtained drug scan was of Valsartan.
c) Preparation of calibration curve in phosphate buffer (pH 6.8): Calibration curve of Valsartan was prepared in buffer of pH 6.8 (in triplicate). Stock solution (100µg/ml) was prepared by dissolving 10mg of drug in 1ml of ethanol in 100ml volumetric flask and further volume was made up by using phosphate buffer pH 6.8. Various dilutions (5µg/ml, 10µg/ml, 15µg/ml, 20µg/ml, 25µg/ml, and 30µg/ml) were further prepared by diluting the stock solution. Absorbance of these solutions was taken by double beam UV spectrophotometer at 250 nm.
1.2 Extraction of China Rose Mucilage from Hibiscus rosasinensis
(M.S. Sokar, A.S. Hanafy, A.H. El-Kamel, S.S. El-Gamal. Pulsatile core-in-cup valsartan tablet formulations: In vitro evaluation. Asian journal of pharmaceutical sciences, 8 (2013) 234-243.
Chaturvedi H, Garg A, Rathore US. Post-Compression Evaluation Parameters for Tablets-An Overview. European Journal of Pharmaceutical and Medical Research. 2017;4(11):526-530).
Extraction Procedure: 1kg Hibiscus rosasinensis (China rose) leaves were procured from the local area of Ambala city, India. Collected leaves were carefully washed and dried under shade for 24 h and then further dried in oven at 30-40°C. Size was reduced with the help of pestle and mortar. Powdered leaves were passed through sieve no. 85 and the powder obtained was weighed. 600g obtained powder was then used for further extraction. Extraction of mucilage includes 3 steps.
Step 1: Extraction of Mucilage: Powdered leaves of Hibiscus rosasinensis were used for the extraction of mucilage. The powdered leaves were placed in 1000ml beaker containing 500ml of distilled water and allowed to boil for 4 h with continuous stirring and heating at 60°C for sufficient release of mucilage in water. Concentrated solution (400ml) was then filtered through muslin cloth in order to separate marc from the filtrate and refrigerated for cooling (3-4°C) for 24 h.
Step 2: Isolation of Mucilage: To the extract (400ml), 1200ml acetone was added for precipitation of mucilage to occur. The precipitated mucilage was washed with acetone and then collected through filtration by muslin cloth. Mucilage was further dried in hot air oven at a temperature of 40°C for 3 h and weighed.
Step 3: Storage: 28.62gm obtained dried mucilage was ground and passed through sieve no 85 and finally stored in air tight container.
1.3 Modification of locust bean gum (MLBG)
[0085] Locust bean gum was placed in porcelain dish and heated on sand bath for 2 h. The polymer was stirred continuously with spatula in order to avoid the charring of the polymer. The temperature of the sand bath was kept at 120 °C. The prepared modified locust bean gum (MLBG) was sieved through sieve no 85 and kept in air tight container away from moisture at room temperature.
(Kulkarni U, Rao NG. Design and Development of Aceclofenac Fast Dissolving Tablets by Novel Hole Technology: A Novel Approach to Decrease the Disintegration Time and Increase the patient compliance. Drug Invention Today. 2011;3(6):91-94.)
EXAMPLE 2: CHARACTERIZATION OF ISOLATED MUCILAGE
(Vidya Sabale, Vandana Patel, and Archana Paranjape. Isolation and characterization of jackfruit mucilage and its comparative evaluation as a mucoadhesive and controlled release component in buccal tablets. Int J Pharm Investig. 2012 Apr-Jun; 2(2): 61–69.
Chaturvedi H, Garg A, Rathore US. Post-Compression Evaluation Parameters for Tablets-An Overview. European Journal of Pharmaceutical and Medical Research. 2017;4(11):526-530.)
a) Organoleptic Characterization: Isolated mucilage was evaluated for organoleptic properties. It was characterized for various parameters like color, odor, taste, texture and fracture. The results are presented in Table 1 below.

Table 1: Organoleptic characterizaton of the mucilage
S. No Organoleptic properties Result

1 Color Brownish
2 Odor Characteristic
3 Taste Mucilaginous
4 Texture Irregular
5 Fracture Rough

b) Swelling Index: It was calculated by weighing a butter paper of size 2X2 cm. Then butter paper was dipped in a petri dish containing water and reweighed. After this 10mg of the powdered sample was kept in a butter paper placing this on a petri dish containing 15 ml of water and the swelling index was calculated after 24 h and the final result was calculated using the formula.


c) pH of Mucilage: The pH of 1% w/v solution in water was determined using digital pH meter.
d) Bulk Density: Apparent bulk density was determined by pouring fixed quantities of the isolated mucilage into a graduated measuring cylinder. The bulk density and weight of the powder was determined. The bulk density was calculated using following formula:


e) Tapped Density: The measuring cylinder containing a known mass of blend was tapped for a fixed time (100 tapping). The minimum volume occupied in the cylinder and weight of the blend was measured. The tapped density was calculated using the following formula:

f) Angle of Repose: Angle of repose (tan ??) was determined by fixed height funnel method. The height (h) of the heap formed was measured and the radius (r) of the cone base was also observed and calculated. Angle of repose was calculated using the equation:

g) Carr’s Consolidation Index (Compressibility) and Hausner’s Ratio: Finely powdered mucilage (5gm) was transferred into a measuring cylinder and compressibility, Hausner’s ratio were calculated using bulk density apparatus.

h) Ash Value: 2 g of powdered mucilage was weighed accurately in a china dish and kept in muffle furnace (500°C) until the powdered sample is converted into ash and then reweighed. Ash value was calculated using the equation.

[0086] The mucilage extract was evaluated for micromeritic study (pH, Bulk Density, Tapped Density, Angle of repose, Carr’s Index, Hausner’s Ratio, Ash Value) and Swelling Index. The results of micromeritics study of mucilage are shown in Table 2 below. The dried mucilage powder showed superior swelling capacity and was pH independent. It demonstrated excellent flow property and compressibility which made it suitable for direct compression tableting.

Table 2: Micromeritics study of mucilage
S. No Parameters Result(mean±SD), n=3
1 Swelling Index (%) 53.17 ± 0.462
2 pH 6.90 ± 0.011
3 Bulk Density (gm/ml) 0.711 ± 0.006
4 Tapped Density (gm/ml) 0.816 ± 0.008
5 Angle of repose (°) 27.33 ± 0.005
6 Carr’s Index (%) 12.9 ± 0.98
7 Hausner’s Ratio (%) 1.14 ± 0.03
8 Ash Value 3%

EXAMPLE 3: SOLID DISPERSIONS
3.1 Preparation of solid dispersions
[0087] Different ratios of Valsartan and ß -cyclodextrin i.e. 1:1, 1:1.5, 1:2, 1:2.5 and 1:3 were prepared using freeze drying method. Initially ß-CD was dissolved in 25ml water with continuous stirring. Valsartan (40 mg) was dissolved in ethyl alcohol (1 mL) and was added to the ß-CD solution in order to allow complexation. This suspension obtained was kept in an ultrasonic bath for 10 min. The mixture was removed and was kept for pre-freezing at a temperature of -20 ºC for 120 min. The pre-freezed sample was kept for freeze drying at a temperature of -70 ºC for 24 h resulting in formation of fine powder. The powder obtained was stored at 4 ºC. The following Table 3 gives the compositions of the different solid dispersions.

Table 3: Composition of various solid dispersions of drug and polymer
Formulation Code Drug (mg) Polymer (mg)
SD 1 40 40
SD 2 40 60
SD 3 40 80
SD 4 40 100
SD 5 40 120

3.2 Evaluation of the various solid dispersions
a. Solubility Studies: The equilibrium solubility of pure Valsartan and solid dispersions was determined in pH 6.8 phosphate buffer at 37oC. For each preparation, an equivalent of 10 mg of drug was added to 25 ml of buffer and 25ml of distilled water in a conical flask and was covered with foil. The flasks were kept in shaking incubator for 48 h at 37±0.5oC. Then, the solution was filtered and the filtrate was assayed spectro-photometrically at 250nm. The results are shown in Table 4 and figure 1.

Table 4: Equilibrium solubility of drug in different solid dispersions
Formulation Equilibrium Solubility (µg/ml)
(mean±SD), n=3
Drug (PD) 100.2381 ± 3.21
SD 1 1057.143 ± 27.54
SD 2 1128.571 ± 40.51
SD 3 1366.667 ± 32.37
SD 4 1626.119 ± 19.51
SD 5 1659.524 ± 18.34
SD 6 1389.435 ± 35.66

[0088] Equilibrium solubility of the drug in phosphate buffer pH 6.8 was found to be 100.2381 ±3.21. It increased with increase in the concentration of ß-CD in the solid dispersion, up to 1:3 ratio of drug and ß-CD, after that the increase in the concentration of ß-CD, decrease in the equilibrium solubility was observed. SD4 and SD5 showed equivalent results, so SD4 was selected for further studies as polymer concentration was less.
b. Content Uniformity: Accurately 140 mg of solid dispersion was dissolved in 10ml ethanol in 100 ml volumetric flask and volume was made up to the mark using phosphate buffer pH 6.8. The solution was filtered and content uniformity was analyzed at 250 nm by UV spectrophotometer. The results are presented in Table 5 below. Content uniformity was observed in the range of 93.1 ± 0.07 to 100.4 ± 0.01 indicating uniform distributions of dispersion of drug in the mixtures.

Table 5: Content uniformity of various Solid dispersions
Formulation % Content Uniformity
(mean±SD), n=3
SD 1 93.1 ± 0.07
SD 2 94.7 ± 0.03
SD 3 98.5 ± 0.04
SD 4 100.4 ± 0.01
SD 5 100.3 ± 0.07

c. Fourier Transform Infrared Spectroscopy: FTIR spectrum of the obtained sample of drug was compared with the standard FTIR spectra of the pure drug and with the excipients used. The ingredients were analyzed for the interactions and compared with the reported literature. FTIR spectra of the pure drug, polymer and solid dispersions are shown in Figures 2, 3 and 4 respectively. The interpretation of the various spectra is given in Tables 6 to 8.

Table 6: Peaks obtained in the FTIR spectra of drug (Valsartan)
Functional group Observed peaks (cm-1) Characteristic peaks (cm-1)
C-H stretch 2964 3000-2850
C=O stretch 1732 1740-1670
C=N stretch 1601 1800-1600
C=C stretch 1410 1400-1600
C-N stretch (tetrazole ring) 1206 1250-1000
C-N stretch (tetrazole ring) 1053 1250-1000
Table 7: Peaks obtained in the FTIR spectra of ß-cyclodextrin
Functional group Frequency (cm-1) Characteristic peaks(cm 1)
O-H stretch 3351 3600-3200
CH2 stretch 2927 2850-3000
C-H bend 1414 1405-1465
O-H bend 1335 1390-1310
C-C stretch 1155 1205-1124

Table 8: Peaks obtained in the FTIR spectra frequency of SD4
Functional group Observed peaks (cm-1) Characteristic peaks (cm-1)
O-H stretch 3338 3600-3200
C-H stretch 2961 3000-2850
C=O stretch 1732 1740-1670
C=N stretch 1610 1800-1600
C=C stretch 1410 1400-1600
C-Nstretch (tetrazole ring) 1204 1250-1000
C-C stretch 1156 1205-1124

[0089] FTIR spectrum of pure drug (Figure 2) shows characteristic peaks 2964 cm-1 resulted from aliphatic C-H stretching. The characteristic peaks at 1732 cm-1 and 1412 cm-1 representing the carboxylic acid C=O stretching and C=C stretching, whereas the C=N stretching caused the peak at 1601.9 cm-1. Finally, the presence of the bands in the region 1206-1053 cm-1 was due to the C-N stretching in tetrazole ring (CN4). FTIR spectrum of ß-CD (Figure 3) shows stretching at 3351 cm-1 , 2927 cm-1 , 1155 cm-1 , and 1031 cm-1 which corresponds to the symmetric and anti symmetric stretching of OH, CH2, C–C and bending vibration of O–H respectively. FTIR spectra of solid dispersions show most of the characteristic peaks of drug (2961, 1732, 1610, 1410, 1204 cm 1) which indicates no interaction of drug with polymer.
d. Differential Scanning Calorimetry: DSC study of drug, polymer and solid dispersions were carried out to study the changes in amorphous to crystalline or vice-versa or any polymorphic changes during formulation of solid dispersions. DSC experiments were conducted on Q20 V24.9 (Perkin Elmer). The samples were sealed in aluminium pans and heated at a constant rate of 1°C/min over a temperature range of 20-250°C. Inert atmosphere was maintained by purging nitrogen gas at a flow rate of 1ml/min.
[0090] The DSC thermograms for pure drug, polymer and solid dispersions are shown in Figures 5, 6 and 7, respectively. The DSC thermogram of valsartan shows a less intense endothermic peak at 101.93 °C with enthalpy of fusion 40.66 J/g corresponding to its melting point, which indicates its crystalline nature. The onset of melting was observed at 95.98 °C. The DSC thermogram of valsartan with ß- cyclodextrin showed a broad peak at 122.74 °C for the drug with enthalpy of fusion 294.4 J/g. The DSC study reveals no significant interaction between valsartan and ß-cyclodextrin used and there was a change in crystallinity of pure valsartan to amorphous state in the solid dispersions. Moreover, the absence of a melting peak of Valsartan in the solid dispersions was taken as an indication that the drug is included in ß- cyclodextrin cavity, leading to a reduction in the overall crystallinity of the system.
e. Scanning Electron Microscopy: Samples of pure drug, polymer and solid dispersion formulations were mounted onto the stubs using double sided adhesive tape and then coated with gold palladium alloy (150-200 Å) using fine coat ion sputter. The samples were subsequently analyzed under the scanning electron microscope for external morphology.
[0091] Scanning electron micrographs of the drug, polymer and solid dispersion 4 are shown in Figures 8, 9, and 10, respectively. The drug (Valsartan) exhibited crystalline form as evident by the specific geometric form in Figure 8. Figure 10, i.e., SEM of SD4, exhibited fall in crystallinity. The particles lost the crystallinity as well as the shape. The amorphous structure was indirect evidence, that the solid dispersions are formed. The edges of the same have gone smooth vis-a-vis the pure drug (Figure 8).
f. X-Ray Diffraction: X-Ray Diffraction patterns were traced employing X-ray diffractometer for the pure drug, polymer and solid dispersion using Ni filtered Cu (K-a) radiations, a voltage of 45 kV, a current of 40 mA. The samples were analyzed over 2? range of 0-50o with scan step size of 0.0170o (2?) and scan step time 25s.
[0092] The presence or absence of crystallinity of drug and polymer was determined by comparing some representative peak heights in the diffraction of the solid dispersion with that of pure drug (Valsartan). The X-RD pattern of drug, polymer and solid dispersions are shown in the Figures 11, 12 and 13 and Tables 9, 10 and 11, respectively. The XRD diffractogram of pure VAL was crystalline, with broad peaks at at 6.6252 and 14.0826 with peak intensities of 100.00 and 14.17 and the area of 432.29 and 10.49 respectively. Diffraction patterns of solid dispersion batch SD4 (Fig 13) showed broader peaks of the diffraction angle of 2? at 10.6773, 12.4968, 14.7004, 17.1309, 18.7966, 19.5877, 20.7779, 21.4648, 22.7523 and 24.28879 with peak intensities of 29.47, 65.19, 100.00, 17.18, 38.78, 40.83, 53.67, 41.07, 21.31, 29.06 and 17.94. The drug peaks at 6.6252° and 14.0826° disappeared when Valsartan was incorporated in SD4, indicating that the drug’s crystalline structure was changed into an amorphous form.

Table 9: Characteristic X-RD peaks of drug
Position (o2?) Relative intensity (%) Area (cts*o2?)
6.6252 100.00 432.29
14.0826 14.17 10.49

Table 10: Characteristic X-RD peaks of polymer
Position (o2?) Relative intensity (%) Area (cts*o2?)
8.9799 26.31 116.94
10.6850 52.91 171.12
12.4620 100.00 267.48
12.6693 77.61 272.52
19.6278 48.98 216.02
20.8739 41.16 229.83
22.8469 47.02 308.52
24.3765 22.77 316.43
26.7992 42.25 311.42
28.7914 10.76 254.25
31.1034 10.63 239.85
34.7260 18.99 299.53

Table 11: Characteristic X-RD peaks of the Solid Dispersions (SD4)
Position (o2?) Relative intensity (%) Area (cts*o2?)
10.6773 65.19 162.29
12.4968 100.00 365.35
14.7004 17.18 43.79
17.1309 38.78 161.64
18.7966 40.83 207.15
19.5877 53.67 260.17
20.7779 41.07 225.80
21.4648 21.31 159.68
22.7523 29.06 196.69
24.2887 17.94 188.67

g. in vitro Dissolution Studies: In vitro dissolution studies of the various dispersions and pure drug were carried out in 900ml of phosphate buffer (pH 6.8) at 37±0.5oC with the stirrer rotation speed of 50 rpm using USP dissolution apparatus using a paddle stirrer (Type II). A 5 ml aliquot of dissolution medium was withdrawn at 5, 10, 15, 20, 25, 30, 45 and 60 min and replaced with same amount of buffer with the help of pipette. The samples were suitably diluted and assayed spectrophotometrically at 250 nm.
[0093] In vitro drug release from various solid dispersions (SD1, SD2, SD3, SD4, SD5) and pure drug (Valsartan) is given in Table 12 and shown in Figure 14. Drug release was found to be increased in various solid dispersions as compared to that of pure drug. The release of pure drug in 30 min was found to be 24% whereas SD1 showed 50% release in 30 min. Maximum dissolution rate was observed in SD4 (93%) indicating that 1:2.5 ratio of drug to polymer was the optimum batch. Increase in the amounts of polymer after that lead to decreased drug release. This may be due to viscous plugs formed at higher concentrations of polymer. This indicates that ß-cyclodextrin can be an alternative matrix for solid dispersions for enhancement of dissolution characteristics of poorly soluble drugs. Cumulative percentage drug release profile of different solid dispersions batches and pure drug is mentioned in Table 12.

Table 12: %CDR vs Time data of pure drug and various SD batches
Time(min) % Cumulative Drug Release (mean±SD), n=3
Drug SD 1 SD 2 SD 3 SD 4 SD 5
0 0.00 0.00 0.00 0.00 0.00 0.00
5 7.25 ± 1.1 22.53 ± 1.4 30.25 ± 1.6 36.57 ± 1.2 44.14 ± 1.5 30.25 ± 2.1
10 10.80 ± 1.2 28.70 ± 1.6 39.35 ± 1.3 41.05 ± 1.8 51.85 ± 1.8 43.36 ± 2
15 13.27 ± 1 35.96 ± 1.9 51.85 ± 1.8 59.88 ± 1.6 73.46 ± 1.4 58.18 ± 1.4
20 17.90 ± 2.1 39.66 ± 1.5 57.72 ± 1.2 68.67 ± 1.2 79.63 ± 1.2 68.52 ± 1.6
25 20.83 ± 2 45.56 ± 1.2 66.67 ± 1.9 76.54 ± 1,8 89.20 ± 1.1 82.72 ± 1.3
30 24.07 ± 1.4 50.15 ± 2.1 72.84 ± 2.2 81.48 ± 1.6 93.98 ± 1.9 89.20 ± 1.7
45 27.62 ± 1.6 55.71 ± 2.1 72.07 ± 2.5 86.11 ± 2.1 95.52 ± 2.1 96.45 ± 1.9
60 29.32 ±1.8 60.34 ± 2.3 76.70 ± 2.2 93.06 ± 2.4 98.69 ± 1.9 97.99 ± 2

EXAMPLE 4: TABLET FORMULATION
[0094] The immediate release tablets comprising solid dispersion were prepared by direct compression technique. Solid dispersions powder equivalent to 140 mg of Valsartan (SD4) was used for further compression into immediate release tablets using different natural and synthetic polymers. The drug to polymer ratio was developed to adjust drug release as per theoretical release profile and to keep total weight of tablet constant for all the fabricated batches under experimental conditions of preparation.

Table 13: Composition of Immediate Release Tablet
Ingredients Composition (mg/tablet)
Valsartan 140
Polymer 15
Sodium Saccharin 4
Magnesium Stearate 2
Talc 1
MCC q. s.
Total weight 250

Table 14: Composition of different batches of tablet formulations
Ingredients F1 F2 F3 F4 F5
Valsartan 140 140 140 140 140
China Rose Mucilage Extract 15 - - - -
MLBG - 15 - - -
CP - - 15 - -
SSG - - - 15 -
Pregelatinized Starch - - - - 15
Sodium Saccharin 4 4 4 4 4
Magnesium stearate 2 2 2 2 2
Talc 1 1 1 1 1
MCC q. s. q. s. q. s. q. s. q. s.
Total 250 250 250 250 250

4.1: Post-Compression Parameters: Tablets were formulated as per the composition above (Table 14) and were evaluated for physicochemical characterization (thickness, disintegration time, hardness, weight variation, friability, drug content, wetting time) and in vitro drug release studies. The results of physicochemical characterization are presented in Table 16.
4.1.1. Physicochemical characterization
a) Thickness: In this three tablets were randomly taken and their thickness and diameters were measured by Vernier Calliper.
b) Weight Variation Test: Twenty tablets were selected and weighed individually. Then the average weight and standard deviation was calculated. Test passes when not more than two tablets deviate from average weight. Limit of weight variation of tablet according to U.S.P is given in the Table 15. (Development and evaluation of immediate release diclofenac sodium suppositories. Sultan T, Hamid S, Hassan S, Hussain K, Ahmed A, Bashir L, Naz S, Maqbool T. Pak J Pharm Sci. 2018 Sep; 31(5):1791-1795.)

Table 15: Limit of Weight Variation according to U.S.P
WEIGHT MAXIMUM PERCENTAGE DIFFERENCE ALLOWED
Less than 130mg ±10
130-324mg ±7.5
More than 324mg ±5
c) Hardness: Hardness or crushing strength is the force required to break a tablet in a diametric compression measured using Monsanto tablet hardness tester. It is expressed in kg/cm2. Hardness helps in knowing ability of the tablet to withstand mechanical shock during handling of tablets.
(Impact of vibration and agitation speed on dissolution of USP prednisone tablets RS and various IR tablet formulations. Seeger N, Lange S, Klein S.AAPS PharmSciTech. 2015 Aug;16(4):759-66.)
d) Friability: Ten tablets were selected and weighed and then placed in friabilator apparatus which rotates at 25 rpm speed for 4 minutes. After 4 minutes tablets were weighed again.


where
W = initial weight of tablet
Wt= after revolution tablet weight
% Friability of tablets less than 1% is considered acceptable.
e) Drug Content Uniformity: Ten tablets are taken and powdered; equivalent weight of drug dose is taken and is transferred to volumetric flask and then buffer is added and absorbance is determined using U.V spectrophotometer.
(Innovation of novel 'Tab in Tab' system for release modulation of milnacipran HCl: optimization, formulation and in vitro investigations. Parejiya PB, Barot BS, Patel HK, Shelat PK, Shukla A. Drug Dev Ind Pharm. 2013 Nov;39(11):1851-63.)
f) In vitro Disintegration Test: The disintegration time was measured using disintegration test apparatus. One tablet was placed in each tube of the basket. The basket with the bottom surface made of a stainless-steel screen (mesh no.10) was immersed in water bath at 37 ± 2 °C. The time required for complete disintegration of the tablet in each tube was determined using a stop watch.
(Innovation of novel 'Tab in Tab' system for release modulation of milnacipran HCl: optimization, formulation and in vitro investigations. Parejiya PB, Barot BS, Patel HK, Shelat PK, Shukla A. Drug Dev Ind Pharm. 2013 Nov;39(11):1851-63.)
g) Wetting Time and Water Absorption Ratio: A piece of paper folded twice was kept in a Petri dish containing 6 ml of purified water and a small amount of Rosaline dye powder. A tablet was placed on the tissue paper. The time required to develop a red color on the upper surface of the tablet was recorded as the wetting time. Test was performed with the same procedure as that of wetting time. In this test initial weight of tablet was taken before placing on petri dish. After complete wetting the wet tablet was weighed. Water absorption ratio, R was determined using the equation:

Where, Wa and Wb were the weights of the tablet before and after water absorption.
( Development of modified-release tablets of zolpidem tartrate by biphasic quick/slow delivery system. Mahapatra AK, Sameeraja NH, Murthy PN. AAPS Pharm. Sci. Tech. 2015 Jun;16(3):579-88.)

Table 16: Evaluation of post compression parameters of various Immediate Release Tablet batches
S. No Parameters Formulation (mean±SD), n=3
F1 F2 F3 F4 F5
1 Disintegration Time (Sec) 26 ± 2 41 ± 1.5 40 ± 2 60 ± 1.5 150 ± 1
2 Hardness
(Kg/cm2) 3.12 ± 0.02 3.00 ± 0.01 3.5 ± 0.05 3.78 ± 0.07 3.9 ± 0.01
3 Thickness
(mm) 3.8 ± 0.2 3.4 ± 0.1 3.2 ± 0.2 3.3± 0.4 3.2 ± 0.5
4 Wetting Time (Sec) 32 ±1.5 44 ±2 35 ± 1 47 ± 2.5 50 ± 1
5 Weight Variation (mg) 248±2.3 246 ± 0.9 247 ± 0.7 248 ± 0.5 246 ± 0.3
6 % Friability 0.55 ±0.02 0.67 ±0.05 0.60 ± 0.01 0.62 ± 0.05 0.88 ± 0.04
7 Drug Content
(%) 98.22 ± 0.2 97.01 ± 0.5 98.66 ± 0.7 97.33 ± 0.4 95.83 ± 0.1
8 Water absorption Ratio (%) 13.19 ± 0.03 16.94 ± 0.05 15.80 ± 0.01 19.32 ± 0.07 25.45 ± 0.08

4.1.2. In Vitro Dissolution Studies: Dissolution study was performed using USP paddle apparatus (Type II), in 900ml of 6.8 pH phosphate buffer by maintaining optimum temperature at 37°C ± 0.5°C and 50 rpm rotational speed. Aliquots of 5ml were taken at specified interval (5, 10, 15, 20, 25, 30, 45 and 60 min) and were replaced with same amount of buffer (pH 6.8 phosphate buffer). Samples were checked under U.V Spectrophotometer at 250nm wavelength. (Innovation of novel 'Tab in Tab' system for release modulation of milnacipran HCl: optimization, formulation and in vitro investigations. Parejiya PB, Barot BS, Patel HK, Shelat PK, Shukla A. Drug Dev Ind Pharm. 2013 Nov;39(11):1851-63)
In vitro drug release profile of different Immediate Release Tablets batches (F1, F2, F3, F4, and F5) and marketed product (Valent) are shown in Table 17 and Figure 15.

Table 17: %CDR vs Time data of Marketed Product and various Immediate Release batches
Time (min) % Cumulative Drug Release (mean±SD), n=3
MP F1 F2 F3 F4 F5
0 0 0 0 0 0 0
5 23.32 ± 1.1 49.85 ±
1.4 44.14 ± 1.6 47.07 ± 1.3 47.38 ± 1.5 30.86 ± 1.2
10 29.78 ± 1.2 60.34 ± 1.8 53.86 ±1.2 57.65 ± 1.1 56.33 ± 1.7 39.81 ± 2
15 36.88 ± 1.8 76.08 ± 2.3 65.12 ± 0.8 70.06 ± 2.1 66.67 ± 1.3 52.93 ± 1.2
20 39.66 ± 2.1 85.65 ± 1.2 80.25 ± 1.4 82.72 ± 2.1 75.15 ± 1.3 62.96 ± 1.6
25 45.99 ± 1.2 94.03 ± 1.4 89.97 ± 1.5 92.21 ± 1.2 81.79 ± 1.7 73.15 ± 1.7
30 50.77 ± 2.3 98.3 ± 2.3 96.45 ± 2.1 96.99 ± 1.5 87.65 ± 1.3 83.02 ± 1.2
45 54.17 ± 1.6 98.87 ± 2.1 97.22 ± 1.8 97.49 ± 1.1 95.68 ± 2.1 89.04 ± 1.9
60 61.88 ± 1.8 99.72 ± 1.3 97.53 ± 2.2 98.3 ± 1.4 97.38 ± 1.9 93.36 ± 2.1

[0095] The drug release for the formulation as per the present invention, F1, was found to be better than the comparative formulations F2-F5 and marketed product (Valent). Thus, the mucilage of Hibiscus rosasinensis or China rose was found to be an effective disintegrant for solid dispersion formulations of Valsartan compared to modified locust bean gum , pregelatinized starch, crospovidone and sodium starch glycolate.
EXAMPLE 5: Drug Release Kinetics
[0096] In order to determine the release model which best describes the mechanism of the drug release in vitro; release data of Valsartan solid dispersions was fitted into zero order, first order, Higuchi, Korsemeyer peppas and Hixson Crowell release models. The release pattern of a certain mechanism was based on the correlation coefficient (r2) for the parameters studied, where the highest correlation coefficient is preferred for the selection of the mechanism of release. The release kinetics of optimized formulation F1 in different models is illustrated in Table 18 and figures 16-20.

Table 18: Drug Release Kinetics of Model fitting in optimized Immediate Release formulation (F1)
Model r2 Slope intercept
Zero order 0.84 1.314 42.88
First order 0.88 0.036 1.84
Higuchi 0.98 0.72 0.036
Hixon-cowel 0.82 0.06 3.8
Korsmeyer-peppas 0.903 0.304 1.506

[0097] Higuchi model has been used to explain the release of soluble and insoluble drug from the matrix. Higuchi kinetics is used where the release occurs by diffusion mechanism .To confirm this, the data was fitted into the Korsemeyer peppas model. The release exponent (n) values from the power equation enlighten the understanding of the release mechanism from the dosage form. The n value obtained ranged between 0.54-0.80 which indicates that the formulations exhibited anomalous (non-fickian) behavior. The drug is released as the polymer swells, relaxes and erodes.
EXAMPLE 6: Stability Studies
Stability studies of optimized formulation (F1) were carried out for one month. Results have been provided in Table 19.

Table 19: Stability studies of optimized formulation (F1)
Specification Initial 15 Days 30 Days
Average weight
250 mg +2%
250
249
248
Hardness
(Kg/cm2) 3.12 3.12 3.10
Drug Content 99.10 98.87 98.80
Disintegration
(sec) 26 27 26

[0098] Optimized formulation batch F1 was found to be stable when stored under stress conditions (40°±2°C/ 75±5% RH).
[0099] The foregoing embodiments are merely illustrative and are not to be taken as limitations upon the scope of the invention. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications may be made without departing from the scope of the invention.

Claims:1. A pharmaceutical formulation for immediate release comprising:
(a) solid dispersions comprising ß-cyclodextrin and Valsartan or pharmaceutically acceptable salts thereof;
(b) mucilage of Hibiscus rosasinensis or China rose; and
(c) at least one pharmaceutically acceptable excipient;
wherein the weight ratio of Valsartan to ß-cyclodextrin is 1:2.5; and
wherein the weight ratio of the mucilage of Hibiscus rosasinensis to the solid dispersions is in the range of 1:8 to 1:10.
2. The formulation as claimed in claim 1, wherein the weight ratio of the mucilage of Hibiscus rosasinensis to the solid dispersions is 1:9.
3. The formulation as claimed in claim 1, wherein the pharmaceutically acceptable excipient is selected from binders, glidants, lubricant, coloring agents, flavoring agents, diluents, bulking agent, stabilizers, emulsifiers, sweeteners and combinations thereof.
4. The formulation as claimed in claim 1, wherein the formulation is administered in a solid dosage form.
5. The formulation as claimed in claim 4, wherein the formulation is administered in the form of a tablet.
6. The formulation as claimed in claim 1, wherein the solid dispersion has solubility in the range of 500µg/ml to 3000µg/ml.
7. The formulation as claimed in claim 1, wherein the formulation releases over 98% drug in less than 30 minutes.
8. The formulation as claimed in claim 1, wherein the formulation is administered in a pharmaceutically acceptable amount to a subject.
9. A process of preparing a pharmaceutical formulation comprising the steps of:
(a) boiling and concentrating powder of Hibiscus rosasinensis in water and thereafter precipitating with acetone to extract mucilage of Hibiscus rosasinensis;
(b) preparing a solid dispersion of Valsartan or pharmaceutically acceptable salts thereof and ß-cyclodextrin by freeze drying; and
(c) mixing mucilage of Hibiscus rosasinensis and at least one pharmaceutically acceptable excipient with the solid dispersion to obtain the pharmaceutical formulation;
wherein the weight ratio of Valsartan to ß-cyclodextrin is 1:2.5; and
wherein the weight ratio of the mucilage of Hibiscus rosasinensis to the solid dispersions is in the range of 1:8 to 1:10.