The present disclosure relates generally to pharmaceuticals. More specifically, the disclosure provides a solid dispersion composition comprising Fenoprofen Calcium, 2-hydroxypropyl-P-cyclodextrin, polyvinylpyrrolidone and a surface active agent. The present disclosure also provides a method of preparation of the composition.
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] Fenoprofen Calcium is an anti-inflammatory analgesic used to treat mild to moderate pain in addition to the signs and symptoms of rheumatoid arthritis and osteoarthritis. It is an arylacetic acid derivative and exists as white crystalline powder. Fenoprofen Calcium has partition coefficient (log P) value of 3.87 and is practically insoluble in water viz. 0.0811 mg/mL; therefore, this drug belongs to class II according to the Biopharmaceutical Classification System (BCS), i.e. drugs with low solubility and high permeability. Low aqueous solubility of Fenoprofen Calcium causes slow drug absorption and therefore low oral bioavailability. Consequently, solubility enhancement of Fenoprofen Calcium is a requisite for enhanced dissolution and amplification of bioavailability. [0004] The inventors of the present disclosure provide a composition for improving the aqueous solubility and consequently the bioavailability of Fenoprofen Calcium.
OBJECTS OF THE INVENTION
[0005] An object of the present disclosure is to provide a solid dispersion composition of Fenoprofen Calcium.

[0006] An object of the present disclosure is to provide a composition of Fenoprofen Calcium that has amplified saturation aqueous solubility and dissolution profile.
[0007] Yet another object of the present disclosure is to provide a method of preparing a solid dispersion composition of Fenoprofen Calcium.
SUMMARY OF THE INVENTION
[0008] 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.
[0009] Aspects of the present disclosure provide a solid dispersion composition of the weakly soluble drug Fenoprofen Calcium by employing highly water soluble polymers.
[0010] In an aspect, the present disclosure provides a solid dispersion composition comprising Fenoprofen Calcium, polyvinylpyrrolidone, 2-hydroxypropyl-P-cyclodextrin and a surface active agent.
[0011] In an embodiment, the composition comprises Fenoprofen Calcium, polyvinylpyrrolidone, 2-hydroxypropyl-P-cyclodextrin and a polysorbate. [0012] In an aspect, the present disclosure provides a method of preparing a solid dispersion composition employing solvent evaporation.
[0013] In an embodiment, the method comprises the steps of: (a) mixing and dissolving Fenoprofen Calcium, polyvinylpyrrolidone, 2-hydroxypropyl-P-cyclodextrin, and a polysorbate in a solvent followed by evaporating the solvent until a dry mixture is obtained; and (b) milling and sifting the dried mixture to give the solid dispersion composition.
[0014] 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
[0015] 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.
[0016] Figures 1(a) and 1(c) provide the contour plots (2D) showing the effect of independent variables, i.e. the constituents - polysorbate 80, Polyvinylpyrrolidone K-30 and 2-hydroxypropyl-P-cyclodextrin on saturation aqueous solubility (ug/ml) (Yl) of the composition as per an embodiment of the present disclosure. Figures 1(b) and 1(d) provide the response surface plots (3D) showing the effect of independent variables, i.e. the constituents - polysorbate 80, Polyvinylpyrrolidone K-30 and 2-hydroxypropyl-P-cyclodextrin on saturation aqueous solubility (ug/ml) (Yl) of the composition as per an embodiment of the present disclosure.
[0017] Figures 2(a) and 2(c) provide the contour plots (2D) showing the effect of the independent variables, i.e. the constituents - polysorbate 80, Polyvinylpyrrolidone K-30 and 2-hydroxypropyl-P-cyclodextrin on Qihr (%)(Y2), i.e. the percentage of drug released in 1 hour from the composition as per an embodiment of the present disclosure. Figures 2(b) and 2(d) provide the response surface plots (3D) showing the effect of the independent variables, i.e. the constituents - polysorbate 80, Polyvinylpyrrolidone K-30 and 2-hydroxypropyl-P-cyclodextrin on Qihr(%)(Y2), i.e. the percentage of drug released in 1 hour from the composition as per an embodiment of the present disclosure.
DETAILED DESCRIPTION OF THE INVENTION
[0018] 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.

[0019] 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. [0020] 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.
[0021] 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. [0022] 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.
[0023] 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
i clearly dictates otherwise. Also, as used in the description herein, the meaning of "in" includes "in" and "on" unless the context clearly dictates otherwise. [0024] 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."
[0025] 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.
i [0026] 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. [0027] 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
i 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. [0028] 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.
[0029] 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. [0030] The headings and abstract of the invention provided herein are for convenience only and do not interpret the scope or meaning of the embodiments. [0031] 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.
[0032] The term, "pharmaceutically acceptable" as used herein refers to a carrier comprised of a material that is not biologically or otherwise undesirable. [0033] 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. [0034] The term "therapeutically effective amount" refers to the amount determined by a medical professional that treats, prevents or ameliorates the condition of a subject without causing any side effects.
[0035] The terms 'drug' and 'Fenoprofen Calcium' have been used interchangeably herein.

[0036] The present disclosure focuses on improving the aqueous solubility of
Fenoprofen Calcium through development of a solid dispersion composition with
highly water-soluble excipients.
[0037] In an embodiment, the present disclosure provides a solid dispersion
composition comprising Fenoprofen Calcium, polyvinylpyrrolidone, 2-
hydroxypropyl-P-cyclodextrin and a surface active agent.
[0038] In an embodiment, the composition comprises Fenoprofen Calcium,
polyvinylpyrrolidone, 2-hydroxypropyl-P-cyclodextrin and a polysorbate.
[0039] In an embodiment, the Fenoprofen Calcium may be present in a range of
about 15%) w/w to about 35% w/w of the composition. In a preferred embodiment,
the Fenoprofen Calcium may be present in a range of about 25% w/w to about
30%) w/w of the composition.
[0040] In an embodiment, the polyvinylpyrrolidone may be present in a range of
about 20%) w/w to about 50% w/w of the composition. In a preferred embodiment,
the polyvinylpyrrolidone may be present in a range of about 25% w/w to about
30%) w/w of the composition. In a preferred embodiment, the
polyvinylpyrrolidone is polyvinylpyrrolidone K-30 (PVP K-30) which is a
hydrophilic amorphous polymer having high aqueous solubility, strong
physiological resistance and decreased toxicity.
[0041] 2-hydroxypropyl-P-cyclodextrin (HP-P-CD) is modified beta-cyclodextrin
which has high aqueous solubility and safety profile. In an embodiment, the 2-
hydroxypropyl-P-cyclodextrin may be present in a range of about 20% w/w to
about 50%) w/w of the composition. In a preferred embodiment, the 2-
hydroxypropyl-P-cyclodextrin may be present in a range of about 25% w/w to
about 30%) w/w of the composition.
[0042] In an embodiment, the polysorbate may be selected from polyoxyethylene
(20) sorbitan monolaurate (polysorbate 20), polyoxyethylene (20) sorbitan
monopalmitate (polysorbate 40), polyoxyethylene (20) sorbitan monostearate
(polysorbate 60), or polyoxyethylene (20) sorbitan monooleate (polysorbate 80).
[0043] In a preferred embodiment, the composition comprises polysorbate 80.
Polysorbate 80, a surface active agent, causes decrease in interfacial tension of

particles of solid dispersions and facilitates enhancement of solubility and dissolution of Fenoprofen Calcium.
[0044] In an embodiment, the polysorbate may be present in a range of about 2% w/w to about 7%> w/w of the composition. In a preferred embodiment, the polysorbate may be present in a range of about 6% w/w to about 7% w/w of the composition.
[0045] The composition has amplified saturation aqueous solubility (ug/ml) and dissolution profile. The composition leads to amorphization, reduction in particle size and therefore increased surface area and wettability which collectively imparts improvement in dissolution. The components together possess a synergistic effect to produce solid dispersions with high solubility and improved dissolution profile which a pure drug- Fenoprofen Calcium does not possess. In an embodiment, the composition increases the bioavailability of the drug. The composition of the present disclosure has good micromeritics. [0046] In an embodiment, the saturation aqueous solubility of the drug may be in the range of about 70ug/mL to about 140ug/mL. In some embodiments, the composition may show up to 26 folds increase in saturation aqueous solubility compared to pure drug.
[0047] In an embodiment, the percentage drug released in one hour from the composition may be in the range of about 60% to about 98%. In some embodiments, the percentage drug release from the composition may be upto 4 to 5 folds higher compared to pure drug.
[0048] In an embodiment, the present disclosure provides a solid dispersion formulation comprising Fenoprofen Calcium, polyvinylpyrrolidone, 2-hydroxypropyl-P-cyclodextrin, a surface active agent, and one or more pharmaceutically acceptable excipient(s).
[0049] In an embodiment, the excipients may be selected from solvent, co-surfactant, coloring agents, coating agents, preservatives, anti-caking agents, sequestrants, anti-oxidants, stabilizers, or combinations thereof. However, a person of skill in the art would understand that any other excipient(s) may be employed without going beyond the spirit and scope of the present disclosure.

[0050] In an embodiment, the solvent may be selected from water, ethanol, methylene chloride, acetone, acetic acid, methyl acetate, isopropyl acetate or combinations thereof. However, a person of skill in the art would understand that any other solvent(s) may be employed without going beyond the spirit and scope of the present disclosure.
[0051] In an embodiment, the co-surfactant may be selected from polyethylene glycol 400, polyethylene glycol 600, propylene glycol or combinations thereof. However, a person of skill in the art would understand that any other co-surfactant(s) may be employed without going beyond the spirit and scope of the present disclosure.
[0052] In an embodiment, the coloring agent may be selected from inorganic or organic agents including titanium dioxide, beta-carotene, indigo carmine, allura red, amaranth, tartrazine, sunset yellow, erythrosine, annatto, lycophene or combinations thereof. However, a person of skill in the art would understand that any other coloring agent (s) may be employed without going beyond the spirit and scope of the present disclosure.
[0053] In an embodiment, the coating agent may be selected from celluloses such as hydroxypropyl methyl cellulose, hydroxypropyl cellulose, and ethyl cellulose; acryls such as methacrylic acid, and ethylacrylate copolymers; vinyls, such as polyvinyl alcohol; sugars such as maltose; or combinations thereof. However, a person of skill in the art would understand that any other coating agent (s) may be employed without going beyond the spirit and scope of the present disclosure. [0054] In an embodiment, the preservative may be selected from sodium benzoate, potassium benzoate, benzoic acid, sorbic acid, or combinations thereof. However, a person of skill in the art would understand that any other preservative(s) may be employed without going beyond the spirit and scope of the present disclosure.
[0055] In an embodiment, the anti-caking agents may be selected from talcum powder, silicon dioxide, or combinations thereof. However, a person of skill in the art would understand that any other anti-caking agent(s) may be employed without going beyond the spirit and scope of the present disclosure.

[0056] In an embodiment, the anti-oxidants may be selected from ascorbic acid, sodium metabisulfite, propyl gallate, tocopherols, or combinations thereof. However, a person of skill in the art would understand that any other anti-oxidants) may be employed without going beyond the spirit and scope of the present disclosure.
[0057] In an embodiment, the sequestrant may be ethylenediaminetetraacetic acid. However, a person of skill in the art would understand that any other sequestrant (s) may be employed without going beyond the spirit and scope of the present disclosure.
[0058] In an embodiment, the formulation may be prepared in a solid dosage form including powder, pill or tablet. In an embodiment, the formulation may be an amorphous powder formulation. Suitable pharmaceutically acceptable excipients may be added for preparing the formulation. The amount and choice of excipient may be made based on the formulation that is being prepared. [0059] In an embodiment, the present disclosure provides a method of preparing a solid dispersion composition employing solvent evaporation. [0060] In an embodiment, the method comprises the steps of: (a) mixing and dissolving Fenoprofen Calcium, polyvinylpyrrolidone, 2-hydroxypropyl-P-cyclodextrin, and a polysorbate in a solvent followed by evaporating the solvent until dry mixture is obtained; and (b) milling and sifting the dried mixture to give the solid dispersion composition.
[0061] In an embodiment, the solvent may be selected from ethanol, water, methylene chloride, acetone, acetic acid, methyl acetate, isopropyl acetate or combinations thereof. In a preferred embodiment, the solvent is ethanol. The solvent may be evaporated at about 80±2°C and -0.09 MPa pressure. [0062] In an embodiment, the method gives the composition in high yield, preferably at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%. [0063] In another embodiment, the present disclosure provides a method of treatment, amelioration or prophylaxis of inflammation and pain by administering a therapeutically effective amount of the composition. In some embodiments, the inflammation may be associated with rheumatoid arthritis or osteoarthritis.

[0064] In yet another embodiment, the present disclosure provides use of a solid dispersion composition as recited above in the treatment or amelioration of inflammation and pain.
[0065] 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
[0066] 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. EXAMPLE 1: Preparation of Fenoprofen Calcium solid dispersion and its optimization using Box-Behnken Design
[0067] Fenoprofen Calcium solid dispersions (SD) compositions were prepared using solvent evaporation. They were further optimized using box-behnken design (BBD) to produce amorphous solid dispersion with amplified saturation aqueous solubility (ug/ml) and dissolution profile.
[0068] Total seventeen Fenoprofen Calcium solid dispersions were manufactured as per the compositions given in Table 1. Solid dispersion of Fenoprofen Calcium was prepared by modified solvent evaporation technique. The weighed amounts of Fenoprofen Calcium (200 mg), HP-P-CD, PVP K-30 and Polysorbate 80 (as

mentioned in Table 1) were dissolved in 50 mL of ethanol in a round-bottomed flask. The solvent was allowed to evaporate using rotary evaporator (Perfit, India) at 100 rpm at 80±2°C and -0.09 MPa pressure until it is completely dry. The dried product was milled and sifted through sieve #44 to obtain a fine solid dispersion composition. For optimization, the levels of independent variables for Fenoprofen Calcium-solid dispersion manufacture are depicted in Table 2.
Table 1 Fenoprofen Calcium solid dispersion production as per Box-behnken
design layout

Solid
dispersion
(SD) 2-hydroxy propyl-
P-cyclodextrin
(mg)(Xl) Polyvinylpyrrolidone K-30 (mg) (X2) Polysorbate 80 (mg)(X3)
1 200 200 40
2 200 600 40
3 600 200 40
4 600 600 40
5 200 400 20
6 200 400 60
7 600 400 20
8 600 400 60
9 400 200 20
10 400 200 60
11 400 600 20
12 400 600 60
13 400 400 40
14 400 400 40
15 400 400 40
16 400 400 40
17 400 400 40

Table 2 Independent and response variables for Fenoprofen Calcium
solid dispersion

Independent variables -1 (Low) 0 (Medium) +1 (High)
Xl= 2-hydroxypropyl-P-cyclodextrin (mg) 200 400 600
X2 = Polyvinylpyrrolidone K-30 (mg) 200 400 600
X3 = Polysorbate 80 (mg) 20 40 60
Response variables Constraints Importance
Yl = Saturation aqueous solubility (ug/ml) Maximize

Y2 = Qihr (%) percentage of drug released in 1 hour Maximize

[0069] Evaluation of various parameters of the compositions: [0070] A) Saturation aqueous solubility (ug/ml) (Yl): Fenoprofen Calcium-SD equivalent to 200 mg Fenoprofen Calcium were transferred to 10 ml of distilled water in screw-capped glass vials, sealed, and placed 24 hours in orbital shaker (Remi, India) at 37°C. The withdrawn aliquots were subsequently centrifuged, washed, diluted and the UV-spectrophotometer was used to measure the Fenoprofen Calcium concentration by recording absorbance at 270 nm. [0071] Statistical and response surface analysis of saturation aqueous solubility (ug/ml) (Yl)
[0072] Saturation aqueous solubility (ug/ml) (Yl) was 76.56 ug/ml for SD-9 (minimum) and 118.43 ug/ml for SD-4 (maximum) of solid dispersion. Statistical analysis was performed using analysis of variance using Design-Expert software, and the results are shown in Tables 3, 4 and 5 below. The R2, F-value and p-value for saturation aqueous solubility (Yl) were 0.9986, 565.70 and < 0.0001. Therefore, second order polynomial model was generated by multiple regression analysis using Design-Expert software.

Yl= 90.87 + 9.7Xi + 7.93X2 + 2.34X3 + I.O8X1X2 + 0.305XiX3 + O.88X2X3 + 7.21Xi2+ 1.78X22-6.33X32
[0073] Model F-value 565.70 (p < 0.05) and lack of fit F-value 4.79 (p > 0.05) for Yl implicated that the model was significant with a noise factor of only 0.01%. The results evidently specified that X\, X2 and X3 have synergistic effect on saturation aqueous solubility. Higher values of Yl at high value of FtP-P-CD (XI), PVP K-30 (X2) and Polysorbate 80 (X3) can be correlated with improved aqueous Fenoprofen Calcium solubility in solid dispersion composition. The relationship between factors and responses can be inferred by contour and response surface plots, as shown in Figure 1. Figures 1(a) and 1(c) provide the contour plots showing the effect of the constituents - polysorbate 80, Polyvinylpyrrolidone K-30 and 2-hydroxypropyl-P-cyclodextrin on saturation aqueous solubility. Figures 1(b) and 1(d) provide the response surface plots showing the effect of the constituents - polysorbate 80, Polyvinylpyrrolidone K-30 and 2-hydroxypropyl-P-cyclodextrin on saturation aqueous solubility.
Table 3 Model summary statistics of saturation aqueous solubility (ug/ml)
(Yl) of Fenoprofen Calcium-SDs

Source Std. Dev. R2 Adjusted R2 Predicted R2 PRESS
Linear 5.50 0.7678 0.7143 0.5188 814.22
2FI 6.20 0.7726 0.6362 -0.1483 1943.06
Quadratic 0.5761 0.9986 0.9969 0.9823 29.87 Suggested
Cubic 0.3555 0.9997 0.9988 * Aliased
Table 4 Lack of fit tests of saturation aqueous solubility (ug/ml) (Yl) of
Fenoprofen Calcium-SDs

Source Sum of Squares df Mean Square F-value p-value
Linear 392.31 9 43.59 344.86 < 0.0001

2FI 384.20 6 64.03 506.59 < 0.0001
Quadratic 1.82 3 0.6059 4.79 0.0821 Suggested
Table 5 Analysis of variance (ANOVA) of saturation aqueous solubility
(ug/ml) (Yl) of Fenoprofen Calcium-SDs

Source Sum of Squares df Mean Square F-value p-value
Model 1689.75 9 187.75 565.70 < 0.0001 significant
XI 752.53 752.53 2267.40 < 0.0001
X2 502.92 502.92 1515.33 < 0.0001
X3 43.80 43.80 131.99 < 0.0001
X1X2 4.64 4.64 13.99 0.0073
X1X3 0.3721 0.3721 1.12 0.3248
X2X3 3.10 3.10 9.33 0.0185
XI2 218.96 218.96 659.73 < 0.0001
X22 13.28 13.28 40.03 0.0004
X32 168.51 168.51 507.73 < 0.0001
Lack of Fit 1.82 3 0.6059 4.79 0.0821 not significant
[0074] B) Qihr (%) (Y2): In-vitro dissolution of Fenoprofen Calcium-SD equivalent to 200 mg of Fenoprofen Calcium was performed using USP dissolution test apparatus type II (Labindia DF 8000, Mumbai, India) in 900 ml phosphate buffer pH 6.8 at 37 ±0.5°C at 50 rpm. A 5 mL aliquot was collected with a syringe filter (pore size, 0.22 mm) at different time intervals up to 1 h. ) Filtered samples were diluted and analyzed at 270 nm using a UV spectrophotometer (Systronics AU-2701, Ahmadabad, India). The percentage of drug released in 1 hour (Qihr) (Y2) was determined. [0075] Statistical and response surface analysis of Qihr (%) (Y2)

[0076] The percentage drug release within 1 hour (Qihr) (%) (Y2) was 61.54% for SD-9 (minimum) and 97.11 % for SD-4 (maximum) of solid dispersion. Statistical analysis was performed using analysis of variance using Design-Expert software, and the results are shown in Tables 6, 7 and 8. The R2, F-value and p-value for Q90 (Yl) were 0.9976, 323.99 and < 0.0001. Therefore, second order polynomial model was generated by multiple regression analysis using Design-Expert software.
Y2= 74.2 + 7.89Xi + 6.56X2 + 2.06X3 + 1.53XiX2 + 0.2XiX3 + 0.235X2X3 + 5.74Xi2+ 1.70X22-5.67X32
) [0077] Model F-value 323.99 (p < 0.05) and lack of fit F-value 3.01 (p > 0.05) for Yl implicated that the model was significant with a noise factor of only 0.01%. The results evidently specified that XI, X2 and X3 have synergistic effect on saturation aqueous solubility. Higher values of Y2 at high value of HP-P-CD (XI), PVP K-30 (X2) and Polysorbate 80 (X3) can be correlated with amorphous
i characteristics of Fenoprofen Calcium-SDs. The relationship between factors and responses can be inferred by contour and response surface plots, as shown in Figure 2. Figures 2(a) and 2(c) provide the contour plots showing the effect of the constituents - polysorbate 80, Polyvinylpyrrolidone K-30 and 2-hydroxypropyl-P-cyclodextrin on Qihr, i.e. the percentage of drug released in 1 hour. Figures 2(b)
) and 2(d) provide the response surface plots showing the effect of the constituents -polysorbate 80, Polyvinylpyrrolidone K-30 and 2-hydroxypropyl-P-cyclodextrin on Qihr, i.e. the percentage of drug released in 1 hour.
Table 6 Model summary statistics of Qihr (%) (Y2) of Fenoprofen
Calcium-SDs

Source Std. Dev. R2 Adjusted R2 Predicted R2 PRESS
Linear 4.68 0.7546 0.6980 0.4899 592.43
2FI 5.25 0.7630 0.6207 -0.2029 1397.07
Quadratic 0.6304 0.9976 0.9945 0.9723 32.17 Suggested
Cubic 0.4622 0.9993 0.9971 * Aliased
I

Table 7 Lack of fit tests of Qihr (%) (Y2) of Fenoprofen Calcium-SDs

Source Sum of Squares df Mean Square F-value p-value
Linear 284.15 9 31.57 147.79 0.0001
2FI 274.44 6 45.74 214.11 < 0.0001
Quadratic 1.93 3 0.6423 3.01 0.1577 Suggested
Table 8 Analysis of variance (ANOVA) of Qihr (%) (Y2) of Fenoprofen
Calcium-SDs

Source Sum of Squares df Mean Square F-value p-value
Model 1158.61 9 128.73 323.99 < 0.0001 significant
XI 497.86 497.86 1252.97 < 0.0001
X2 344.66 344.66 867.42 < 0.0001
X3 33.87 33.87 85.23 < 0.0001
X1X2 9.33 9.33 23.49 0.0019
X1X3 0.1600 0.1600 0.4027 0.5459
X2X3 0.2209 0.2209 0.5559 0.4802
XP 138.76 138.76 349.23 < 0.0001
X22 12.11 12.11 30.47 0.0009
X32 135.21 135.21 340.28 < 0.0001
Lack of Fit 1.93 3 0.6423 3.01 0.1577 not significant
EXAMPLE 2: Determination of optimized Fenoprofen Calcium-SD using Design-Expert software
[0078] Based on the studies, the solid dispersion composition comprising of 200 mg Fenoprofen Calcium, 200 mg 2-HP-P-CD, 200 mg D PVP K-30 and 45.36 mg Polysorbate 80 was the optimized composition. Saturation aqueous solubility (ug/ml) and Qihr (%) of optimized composition were determined in comparison to pure drug, Fenoprofen Calcium. The Fenoprofen Calcium saturation aqueous solubility was increased from 2.4±0.89 to 121.25±2.23 ug/ml through fabrication of the solid dispersion composition. This indicated approximately 26-fold enhancement of saturation aqueous solubility of Fenoprofen Calcium. The

percentage cumulative drug release from Fenoprofen Calcium and optimized
composition was found to be 19.84% and 97.23 % within 1 h (Qihr), respectively
(*p < 0.05). This indicated a 4.9-fold enhancement of dissolution of Fenoprofen
Calcium.
[0079] Evaluation of optimized Fenoprofen Calcium solid dispersion
[0080] Percent yield: The optimized Fenoprofen Calcium-SD recovered by
sieving through sieve # 44 was weighed accurately, and the percentage yield was
determined using the formula:
Yield = [(a/£ + c)] X 100 Eq. 1
where 'a' is weight of composition produced, 'b' is Fenoprofen Calcium weight taken for composition fabrication, and 'c' is total weight of excipients (HP-P-CD, PVP K-30 and Polysorbate 80) taken for solid dispersion production. The process yield of optimized Fenoprofen Calcium-SD was 95.11±1.33%. [0081] Angle of repose and compressibility index (CI): The angle of repose (9) and compressibility index (CI) of optimized composition were determined using the static funnel method and the bulk density apparatus, respectively, and measured using the following formulas.
tan 0 = - Eq. 2
r 1
„T tapped density-bulk density . __ _, _
CI = —— -^ -X100 Eq.3
tapped density
[0082] The angle of repose and compressibility index for optimized composition was 11±0.34 and 14±2%, respectively which illustrated excellent micromeritic characteristics of the composition.
[0083] Percentage drug content: The percentage drug content was determined by dissolving an accurate quantity of optimized composition equivalent to 200 mg of Fenoprofen Calcium in phosphate buffer, pH 6.8. The sample was subjected to analysis using UV spectrophotometer (Shimadzu, Kyoto, Japan) at 270 nm. The drug content of optimized composition was measured using equation 4. The drug content of optimized composition was 97.28±1.56%.
„, „ Actual drug content ..,-,,-, -^
% Drug content = -f x 100 Eq. 4
Theoretical drug content

[0084] Thus, Fenoprofen Calcium solid dispersion compositions comprising polyvinylpyrrolidone, 2-hydroxypropyl-P-cyclodextrin and polysorbate 80 can be successfully utilized for augmentation of solubility and dissolution. [0085] The foregoing embodiments are merely illustrative and are not to be taken i 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.
) ADVANTAGES OF THE PRESENT DISCLOSURE
[0086] An object of the present disclosure is to provide a composition for increasing the solubility and bioavailability of Fenoprofen Calcium. [0087] Another object of the present disclosure is to provide a solid-dispersion composition with improved drug release profile.

We Claim:

1. A solid dispersion composition comprising Fenoprofen Calcium,
polyvinylpyrrolidone, 2-hydroxypropyl-P-cyclodextrin and a polysorbate.
2. The composition as claimed in claim 1, wherein the polysorbate is selected from polyoxyethylene (20) sorbitan monolaurate (polysorbate 20), polyoxyethylene (20) sorbitan monopalmitate (polysorbate 40), polyoxyethylene (20) sorbitan monostearate (polysorbate 60), or polyoxyethylene (20) sorbitan monooleate (polysorbate 80).
3. The composition as claimed in claim 1, wherein the Fenoprofen Calcium is present in a range of 15% w/w to 35% w/w of the composition.
4. The composition as claimed in claim 1, wherein the polyvinylpyrrolidone is present in a range of 20% w/w to 50% w/w of the composition.
5. The composition as claimed in claim 1, wherein the 2-hydroxypropyl-P-cyclodextrin is present in a range of 20% w/w to 50% w/w of the composition.
6. The composition as claimed in claim 1, wherein the polysorbate is present in a range of 6% w/w to 7% w/w of the composition.
7. The composition as claimed in claims 1-6, wherein the composition comprises Fenoprofen Calcium in a range of 25% w/w to 30% w/w of the composition; polyvinylpyrrolidone in a range of 25% w/w to 30% w/w of the composition, 2-hydroxypropyl-P-cyclodextrin present in a range of 25% w/w to 30% w/w of the composition, and polysorbate 80 present in a range of 6% w/w to 7% w/w of the composition.
8. A solid dispersion formulation comprising Fenoprofen Calcium,
polyvinylpyrrolidone, 2-hydroxypropyl-P-cyclodextrin, a polysorbate, and one or
more pharmaceutically acceptable excipient(s).
9. A method of preparing a solid dispersion composition comprising the steps of:
(a) mixing and dissolving Fenoprofen Calcium, polyvinylpyrrolidone, 2-
hydroxypropyl-P-cyclodextrin, and a polysorbate in a solvent followed by

evaporating the solvent until dry mixture is obtained; and (b) milling and sifting
the dried mixture to give the solid dispersion composition.
10. The method as claimed in claim 9, wherein the solvent is ethanol.