preparation and characterization of spironolactone solid dispersions using hydrophilic carriers

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Asian Journal of Pharmaceutical Sciences 2012, 7 (1): 40-49

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Preparation and characterization of spironolactone solid dispersions using hydrophilic carriers

Shreya Shah, Sachi Joshi, S. Lin, P. L. Madan*

St. Johns University, College of Pharmacy, Queens, New York, USA Received 2 November 2011; Revised 28 November 2011; Accepted 23 December 2011

_____________________________________________________________________________________________________________

Abstract

This investigation was undertaken to improve dissolution of spironolactone which shows poor bioavailability due to its poor solubility in the gastrointestinal fluids. Polyethylene glycol (PEG 6000), polyvinylpyrrolidone (PVP K30) and Poloxamer 407 were used as hydrophilic carriers at various spironolactone:polymer ratios to prepare solid dispersions using solvent evaporation method. Physical mixtures of corresponding ratios were also prepared for comparison. The order of dissolution enhancement was Poloxamer 407 > PVP K30 > PEG 6000 in solid dispersions as well as in physical mixtures. Dissolution enhancement was significantly greater in solid dispersions than in physical mixtures. Apparent equilibrium solubility studies of spironolactone in solid dispersions showed about 1.5-fold increase in solubility of spironolactone containing PEG 6000, 3-fold increase containing PVP K30 and 9-fold increase containing Poloxamer 407 dispersions at 1:7 drug: polymer ratio. At high polymer concentration, PVP K30 solid dispersions appeared as glass solution while PEG 6000 and Poloxamer 407 solid dispersions show presence of some crystallinity. Detection of hydrogen bonding in Poloxamer 407 and PVP K30 dispersions from FT-IR studies suggests formation of a molecular dispersion. PVP K30 was most effective in achieving amorphization of spironolactone while Poloxamer 407 was most effective in improving dissolution of spironolactone perhaps due to micellar solubilization.

Keywords: Spironolactone solid dispersions; Equilibrium solubility; Dissolution rate; Polyvinylpyrrolidone; Poloxamer 407____________________________________________________________________________________________________________

1. Introduction

The enhancement of oral bioavailability of poorly soluble drugs remains one of the most challenging aspects of drug product formulation especially in view of the fact that of all the newly discovered drug entities; more than 40% are lipophilic in nature and fail to reach the market due to their poor solubility. Several strategies have been used to improve solubilization and dissolution rate of poorly soluble substances. Most of these strategies fall into one or more of the following three categories: (i) change in the nature of solvent environment, e.g., use of co-solvent systems, emulsification, micellization, etc., (ii) change in the chemical identity of the dissolving solute, e.g., salt formation, complexation, and pro-drug approach, and (iii) physical change of the drug substance, e.g., particle size reduction and solid dispersion [1].

Preparation of a solid dispersion formulation has been successfully used to increase solubility and dissolution rate of poorly soluble drugs using hydrophilic carriers. A drug in the solid dispersion can disperse molecularly in

amorphous clusters or in microcrystalline particles within the crystalline or amorphous matrix [2,3]. Solid dispersions offer many advantages, including greater reduction in the particle size compared to conventional mechanical milling, improved wettability of the powder, generation of particles with higher porosity, and presence of powder in the amorphous state, all of which may contribute to enhance dissolution rate and solubility of the poorly soluble compound. Therefore, dissolution enhancement from solid dispersions depends on the physical state and distribution of the drug within the carrier molecules and consequently on (i) the method of preparation of the solid dispersion, (ii) drug and polymer interactions, as well as (iii) physicochemical properties of the drug and carrier. The availability of a limited number of marketed drug products utilizing solid dispersion technology is the direct implication of poor understanding regarding (a) solid state structure of solid dispersion, (b) drug release mechanism from solid dispersions, (c) stability of solid dispersion, and (d) in-vitro: in-vivo correlation of drug release from solid dispersions drug absorption from a solid dispersion formulation [4].

The most popular polymeric carriers used for solid dispersion formulation are polyethylene glycol (PEG) and polyvinylpyrrolidone (PVP) due to their water solubility and ability to form solid solution [5]. Recently, Poloxamers have also shown promise to be excellent

__________*Corresponding author. Address: St. Johns University, College of Pharmacy, Queens, New York 11439, USA. Tel: +1-718-9906242 E-mail: [email protected]

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carriers for the preparation of solid dispersions because Poloxamers have the capability to alter physical properties such as hydrophobicity, surface charge, flocculation/dispersion, floatation and wetting properties [6,7].

Spironolactone is a potassium sparing diuretic and it is used to treat primary hyperaldosteronism, hypokalemia, and various edematous conditions. It possesses low aqueous solubility in the gastrointestinal fluids which results in variable dissolution rate and incomplete oral bioavailability[8,9]. Micronization [10] and complexation with -cyclo-dextrin [11] have shown to increase spironolactone bio-availability by increasing its dissolution rate. Recently, solid dispersions of spironolactone with porous silica [12] and microparticles with gelucire 44/14, a surface active carrier [13], were reported to improve dissolution characteristicsof spironolactone. An earlier investigation reported the use of PEG as a hydrophilic carrier to prepare solid dispersions of spironolactone [14]. Due to the advances of the solid dispersion approach, the objective of the present investigation was to examine solubility and dissolution characteristics of spironolactone from solid dispersions prepared with selected hydrophilic carriers such as PEG 6000, PVP K30, and Poloxamer 407. In addition, solid dispersions were characterized in order to understand drug-carrier interactions and mode of incorporation of spirono-lactone within the selected water-soluble matrices. The solid dispersions of spironolactone were then characterized using differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD) and Fourier transform infrared spectroscopy (FT-IR) in order to evaluate state of the drug as well as drug and polymer interactions.

2. Materials and methods

2.1. Materials

Spironolactone was purchased from Santec Chemicals Corp. (Fresh Meadows, NY, USA). Poloxamer 407 was purchased from Spectrum Chemical Mfg. Corp. (Gardena, CA, USA). Polyethylene glycol (PEG 6000) and polyvinylpyrrolidone (PVP K30) were bought from Fluka Chemicals Corp. (Milwakee, WI, USA) and anhydrous ethanol was purchased from Alfa-Aesar (Ward Hill, MA, USA). All chemicals were of analytical or technical grade and were used as received without further treatment.

2.2. Solubility studies

Solubility studies were performed using the method of Higuchi and Connors [15]. Solutions of polymers (PEG 6000, PVP K30, and Poloxamer 407) ranging in concen-trations from 1 to 10% (w/v) (in 1% w/v increments) were prepared in 0.1 M hydrochloric acid. To 10 ml of each of these solutions contained in screw-capped vials, 10 mg of

spironolactone was added. The vials were screw-capped and shaken (40 strokes/min) at 25C in a wrist action shaker with temperature controlled water bath (Model 75, Burell Scientific, PA, USA). After 48 h, samples were filtered, suitably diluted with 0.1 M hydrochloric acid and analyzed at 243 nm using a UV double beam spectrophotometer (DU Series 700, Beckman Coulter, Inc., Brea, CA, USA).

2.3. Preparation of solid dispersions

To prepare solid dispersions, appropriate quantities of spironolactone and polymers at ratios of 1:1, 1:3 and 1:5, respectively, were accurately weighed and mixed well in a glass mortar for 5 min. Anhydrous ethanol (20 l per mg of spironolactone) was added to this physical mixture, and the mixture was heated on a hot plate at 75C for 3 min. The mixture was immediately cooled on an ice bath for 5 min. The precipitates were dried in a vacuum desiccator for 48 h for removal of residual solvent and then passed through a #30 sieve (600 m) before analysis. For comparison purposes, physical mixtures having the same ratios of spironolactone and polymer were prepared by gently mixing spironolactone and the polymer in a glass mortar, and the mixtures were then passed through a #30 sieve. The composition of these formulations and their corresponding codes are outlined in Table 1.

2.4. In-vitro dissolution studies

All in-vitro dissolution studies were carried out using 1000 ml of 0.1 M hydrochloric acid at 37 1C as the dissolution medium in a USP Dissolution Basket Apparatus (Distek Model Evolution 6100, North Brunswick, NJ, USA) at a stirring speed of 75 rpm. Accurately weighed

ExcipientsPhysical mixture

Solid dispersion

Drug:polymer ratio

PEG 6000

PM PEG 1:1 SD PEG 1:1 1:1



PVP K30

PM PVP 1:1 SD PVP 1:1 1:1



Poloxamer 407

PM P407 1:1 SD P407 1:1 1:1

PM P407 1:3 SD P407 1:3 1:3

PM P407 1:5 SD P407 1:5 1:5

Table 1Composition and codes of physical mixtures and solid dispersions.

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solid dispersions and physical mixtures containing 40 mg of spironolactone were used for dissolution studies. Sink conditions were not maintained because the focus of this investigation was to evaluate solubility of spironolactone. Five milliliter samples of dissolution medium were withdrawn at predetermined intervals and immediately replaced with an equal volume of the dissolution medium (maintained at 37 1C) in order to maintain constant volume of dissolution medium. The withdrawn samples were filtered and analyzed for spironolactone content at 243 nm and cumulative percentage of spironolactone dissolved was calculated. The amount of spironolactone removed in each sample was compensated in the calculations. All experiments were performed in triplicate. From the dissolution profiles, dissolution efficiency (DE120) of formulations was calculated as area under the curve of dissolution profile between two time points expressed as the percentage of curve at maximum possible dissolution over the same time period [16]. In this study dissolution efficiency from 0 to 120 min (expressed as %DE120) denotes the percentage of the area of the rectangle described by 100% dissolution in the same time. The function Area below curve in SigmaPlot 10.0 software was used to calculate area under the curve.

2.5. Apparent equilibrium solubility

Equilibrium solubility studies were carried out by accurately weighing and adding solid dispersion formu-lations containing 40 mg of spironolactone to 10 ml of 0.1 M hydrochloric acid contained in screw capped vials. The vials were shaken on a wrist action shaker in a temperature controlled water bath at 25C. After 24 h, samples were centrifuged (Model 228, Fisher Scientific, Dubuque, IA, USA) at 3400 rpm for 15 min. The super-natant solution was filtered and the filtrate was analyzed. Equilibrium solubility studies were also carried out for spironolactone powder to serve as a control.

2.6. Physical characterization

2.6.1. Differential scanning calorimetry (DSC)

DSC analysis of prepared solid dispersions was per-formed using Perkin-Elmer DiamondTM DSC (Perkin Elmer, Norwalk, CT, USA) with an Intracooler 2P as a cooling device. Samples were accurately weighed (23 mg) in aluminum pans, sealed and thermograms were obtained at the heating rate of 10C per min up to a temperature of 220C. Ultrahigh purity nitrogen was used as the purge gas at a flow rate of 20 ml/min. Indium was used as a reference standard and Pyris software 2.04 (Perkin Elmer, Norwalk, CT, USA) was used for the data analysis.

2.6.2. Powder X-ray diffraction (PXRD)

Shimadzu X-ray diffractometer (LabX XRD 6000, Shimadsu Scientific Instruments, Columbia, MD, USA) was used for the evaluation of type of the solid dispersion. The samples were exposed to CuKa radiation under 30 mA current and 40 kV voltage. The scanning angle ranged from 5 to 40 of 2 and steps were 0.02 of 2/s.

2.6.3. Fourier transform infrared spectroscopy (FT-IR)

A Perkin-Elmer Spectrum One FT-IR Spectrometer (Perkin Elmer, Norwak, CT, USA) with LiTaO3 detector was used for infrared analysis. The potassium bromide discs were prepared by mixing a small amount of the sample with potassium bromide and powder mixture was compressed to form the disc. Resolution of 4 cm-1 was used and scanned over a frequency range of 4000450 cm-1. Perkin Elmer Spectrum v5.3.1 (Perkin Elmer, Norwak, CT, USA) was used for data analysis.

2.7. Statistical analysis

Statistical analysis among formulations was performed by one way ANOVA followed by Tuckeys multiple comparison test using GraphPad Prism software (GraphPad Software Inc., La Jolla, CA, USA) and P < 0.05 was used as the criterion to assess statistical significance.

3. Results and discussion

3.1. Solubility studies

The solubility of spironolactone was determined at 25C and at 37C in purified water as well as in aqueous buffer solutions at pH 1, pH 4, and pH 6.8. The solubility of spironolactone in purified water at 25C was 27.4 1.2 g/ml, which is in agreement with the values published in the literature [13]. The solubility of spironolactone in purified water at 37C as well as in other acidic solutions was very similar to the solubility in purified water at 25Cindicating that the solubility of spironolactone is not influenced either by the change in temperature or by the change in pH of the solution.

The solubility of spironolactone in aqueous solutions of the three selected polymers at different concentrations is shown in Fig. 1. The solubility increased linearly, though marginally in the PEG 6000 solutions (R2 = 0.9932 and slope = 2.72) suggesting very weak interactions between spironolactone and PEG 6000. Solutions of PVP K30 exhibited linear and significantly greater increase in the solubility of spironolactone as the concentration of PVP K30 was increased (R2 = 0.9969, slope = 12.6)

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signifying approximately 5-fold greater solubility than that obtained in the PEG 6000 solutions. This might be attributed to improved wetting in the presence of PVP K30 or association between the functional groups of PVP K30 and spironolactone [17-19]. The solubility of spironolactone was found to be highest in Poloxamer 407 solutions. The increase was linear in the Poloxamer 407 concentration range of 1%5% (w/v), with a slope of 16.22 which indicates approximately 6-fold enhancement in the solubility of spironolactone compared to that of PEG 6000. At Poloxamer 407 concentration greater than 5% (w/v), the solubility increased enormously. Compared to PEG 6000, the increase in solubility was about 9-fold at 7.5% (w/v) and about 14-fold at 10% (w/v) Poloxamer 407 concentrations, respectively. This solubility enhancement might be attributed to the surface active property of Polaxamer 407 and formation of more soluble complex, and possibly micellar solubilization [18].

The higher solubility of spironolactone in the solutions of the carriers suggests greater miscibility of spirono-lactone into the carrier and thus higher probability of solid solution formation during the formulation of the solid dispersion.

3.2. In-vitro dissolution

The dissolution profiles of micronized spironolactone powder, physical mixtures and solid dispersions of spirono-lactone in 0.1 M hydrochloric acid are shown in Fig. 2 and their dissolution efficiency as well as percentage of spironolactone dissolved in 120 min are outlined in Table 2. Micronized spironolactone powder showed only 15% spironolactone dissolution and 9% dissolution efficiency in 120 min. Results in Fig. 2 suggest that all physical mixtures (open symbols) increased dissolution efficiency significantly as compared to that of spironolactone in powder form. As the concentration of polymer increased, the dissolution efficiency also increased significantly (P < 0.001) due to enhanced wetting of spironolactone particles in the presence of hydrophilic groups of polymers. Furthermore, these results also suggest that all solid dispersions of spironolactone (closed symbols) exhibited increased dissolution efficiency significantly as compared to their respective physical mixtures (open symbols). On the other hand, as displayed in Fig. 2A, solid dispersions of spironolactone using PEG 6000 (closed symbols) showed increased initial dissolution rate compared to respective physical mixtures (open symbols); but this extent of dissolution of spironolactone was improved only marginally. PVP K30 solid dispersions of spironolactone at 1:1 (closed circle) and 1:3 (closed square) spironolactone:polymer ratios exhibited greater dissolution efficiency compared to that of spironolactone powder (Fig. 2B). However, dissolution efficiency at higher ratio, e.g., 1:5 spironolactone:polymer

Concentration of polymer (%, w/v)

0 2 4 6 8 10

Con

cent

rati

on o

f sp

iron

olac

tone

(g/

ml)

0

50

100

150

200

250

300PEG 6000PVP K30Poloxamer 407

)11

(R

2ln212

1

rrTM

CC U

J

Fig. 2. Dissolution profiles of spironolactone from physical mixtures and solid dispersions containing (A) PEG 6000; (B) PVP K30; and (C) Poloxamer 407, in 0.1 M hydrochloric acid at 25C (data shown as mean standard deviation, n = 3).

Fig. 1. Solubility of spironolactone in aqueous solutions of PEG 6000, PVP K30, or Poloxamer 407 at 25C (data shown as mean standard deviation, n = 3).

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ratio (closed triangle) did not exhibit further increase, but it decreased. Also, physical mixture of spironolactone (open triangle) with PVP K30 at 1:5 ratio did not show further significant enhancement in the dissolution efficiency as compared to that at 1:3 ratio (P > 0.05). Both Poloxamer 407 physical mixtures and solid dispersions of spironolactone at all drug:polymer ratios evaluated showed significant enhancement in dissolution efficiency compared to that of the powder form of spironolactone (Fig. 2C). It is interesting to note that increasing the spironolactone:polymer ratios to higher levels, such as 1:3 (square symbols) and 1:5 (triangle symbols), the dissolution efficiency of both physical mixture and solid dispersions of spironolactone did not show further significant enhancement. Also, spironolactone dissolution from all solid dispersions of spironolactone reached a plateau at around 6075 min of dissolution and complete spironolactone dissolution was not obtained in any formulation at the end of the 120 min studies.

In order to compare the type of polymers used in the current investigation, dissolution profiles showing optimal dissolution of spironolactone were replotted and are shown in Fig. 3. Poloxamer 407 physical mixtures and solid dis-persions of spironolactone showed significant enhance-ment in dissolution efficiency compared to that of other two polymers. The rank order of dissolution enhancement was Poloxamer 407 > PVP K30 > PEG 6000.

The low dissolution efficiency of pure spironolactone indicates its poor aqueous solubility and wetting. Enhanced dissolution from physical mixtures of spironolactone may be attributed to deaggregation and increased wetting of spironolactone due to the presence of the polymer. The hydrophilic polymer undergoes dissolution immediately upon exposure to the dissolution medium and attains high concentration in the diffusion layer of the drug [20,21]. The dissolved polymer then increases dissolution of drug in the diffusion layer and therefore increases dissolution rate of spironolactone [22]. Increase in dissolution efficiency in the formulations containing PEG 6000 appears to be due to increased dissolution rate resulting from wetting property attributed to its hydrophilic oxyethylene groups. PVP K30 showed better dissolution than PEG 6000 suggest-ing greater spironolactone and polymer interactions and miscibility compared to PEG 6000. However, dissolution efficiency was decreased at higher PVP K30 concen-trations suggesting built up of viscosity in the diffusion layer around the dissolving spironolactone particles that retarded further spironolactone dissolution [23]. Poloxamer 407 was able to enhance dissolution efficiency significantly more than other two polymers due to the surface active property of Poloxamers. Below critical micelle concentration (CMC), it reduces surface tension between spironolactone particles and aqueous medium and above CMC (0.0076% w/v, at 37C), it forms micelles

and dissolves entrapped hydrophobic spironolactone particles [7,17,24,25]. Significantly greater dissolution efficiency of solid dispersions compared to that of physical mixtures even at low spironolactone:polymer ratios can be attributed to decrease in particle size of spironolactone, formation of disordered structure as well as spironolactone and polymer interactions [4,24,26]. Reduced dissolution rate after 6075 min of dissolution suggests formation of spironolactone rich layer around spironolactone particles or reagglomeration of dissolved particles.

3.3. Apparent equilibrium solubility

As shown in Fig. 4, the equilibrium solubility of spironolactone in 0.1 M hydrochloride acid at 25C was found to be 28 g/ml. Solid dispersions exhibited

Fig. 3. Comparison of the optimal dissolution profiles of spirono-lactone from physical mixtures and solid dispersions of spirono-lactone incorporated using different type of polymer in 0.1 M hydrochloric acid at 25C (data shown as mean standard deviation, n = 3).

Fig. 4. Apparent equilibrium solubility of spironolactone from solid dispersions of spironolactone in 0.1 M hydrochloric acid at 25C (data shown as mean standard deviation, n = 3).

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increase in apparent solubility of spironolactone with increasing polymer ratios in all three polymers. The PEG solid dispersions of spironolactone showed least enhance-ment in the apparent solubility of spironolactone while Poloxamer 407 solid dispersions showed highest enhance-ment. Marginal enhancement in equilibrium solubility from the PEG solid dispersions is suggestive of the formation of non-interacting solid dispersion. The apparent solubility ofsolid dispersions at 1:5 spironolactone:polymer ratio of PEG 6000, PVP K30 and Poloxamer 407 showed approximately 1.5-fold, 2.5-fold and 6-fold enhancement, respectively, than that of spironolactone powder, suggestinggreater solubility of spironolactone in a medium contain-ing PEG 6000, PVP K30 or Poloxamer 407.

The average particle size of the micronized spirono-lactone was 2.21 m and further reduction in particle size (less than 12 m) in solid dispersion may have also contributed in improving equilibrium solubility due to high free energy per unit mass as described by Ostwald-Freundlich equation [27,28].

In this equation C1 and C2 represent solubility of particles of radii r1 and r2, respectively, M is the molecular weight, is surface energy of the solid, is density of the solid, R is gas constant, and T is absolute temperature. During the preparation of solid dispersions, spironolactone powder is reduced to its molecular size, thus reducing the particle size of powder spironolactone. Based on the increase in solubility, this equation predicts that the particle size of spironolactone was reduced to 1.17 m in PEG solid dispersions, 0.732 m in PVP K30 dispersions, and 0.446 m in Poloxamar dispersions. Similar results (increase in solubility) were reported with nanoparticle formulations [29,30].

3.4. Differential scanning calorimetry

As shown in Fig. 5, the micronized spironolactone powder exhibited a single sharp endothermic peak at 212.33C with fusion enthalpy of 45.74 J/g. PEG 6000 and Poloxamer 407 showed endothermic peaks at 62.36C and51.66C, respectively, while PVP K30 did not show any endothermic peak because of its amorphous nature. PVP K30 exhibited glass transition temperature at 175C. The position of endothermic peaks of PEG 6000 and Poloxamer 407 was maintained in all solid dispersions of spirono-lactone. Solid dispersion of spironolactone containing PEG 6000 showed the presence of spironolactone endotherm at the 1:1 spironolactone:polymer ratio with H value of 8.54 J/g which is significantly lower compared to that of the spironolactone powder. All other solid dispersions of spironolactone showed absence of spironolactone endotherm suggesting formation of

amorphous spironolactone. PVP K30 solid dispersions of spironolactone showed presence of a single Tg suggesting formation of solid solution.

Lowering and absence of spironolactone endotherm suggest formation of solid dispersion with all three polymers. Presence of single Tg in PVP dispersions suggests formation of solid solution. Absence of spironolactone endotherm in physical mixture of spironolactone suggests dissolution of spironolactone microcrystals within the molten polymer due to heating during analysis. Such phenomenon has been reported previously and that is the limitation of DSC analysis because it is an invasive method, and heating the sample during analysis dissolves crystals into the molten polymer [18,31].

3.5. Powder X-ray diffraction

Solid dispersions as well as physical mixtures of spironolactone were analyzed for comparison and nullify dilution effect. Powder X-ray diffraction patterns of pure spironolactone, each polymer, physical mixtures and solid dispersions of spironolactone are displayed in Fig. 6. Spironolactone powder showed sharp and high intensity peaks at 2 of 9, 11.2, 12, 13.3, 15.8, 16.2, 17, 18 and 20 indicating its highly crystalline state. PEG 6000 and Poloxamer 407 exhibited characteristic PXRD peaks at 19 and 22.5 of 2 corresponding to crystalline polyoxyethylene groups while PVP K30 exhibited halo pattern characteristic of amorphous materials. The position of characteristic peaks of crystalline polymers was not changed in physical mixtures and solid dispersions of

20 60 100 140 180 220

Temperature (C)

Hea

t flo

w

(A)

(C)

(D)

(E)

(B)

(G)

(F)

Fig. 5. DSC thermograms of (A) spironolactone; spironolactone: PEG 6000 solid dispersions at (B) 1:1; and (C) 1:3 levels; spironolactone: PVP K30 solid dispersions at (D) 1:1; and (E) 1:3 levels; and spironolactone: Poloxamer 407 solid dispersions at (F) 1:1; and (G) 1:3 levels.

Concentration of polymer (%, w/v)

0 2 4 6 8 10

Con

cent

rati

on o

f sp

iron

olac

tone

(g/

ml)

0

50

100

150

200

250

300PEG 6000PVP K30Poloxamer 407

)11

(R

2ln212

1

rrTM

CC U

J

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1 1

Fig. 6. Powder X-ray diffraction patterns of physical mixtures and solid dispersions of spironolactone containing PEG 6000, PVP K30 and Poloxamer 407 at various concentrations.

10 15 20 25 30 35 40 10 15 20 25 30 35 40

SD P407 1:5

SD P407 1:3

SD P407 1:1

SD PEG 1:1

Poloxamer-407

SD PVP 1:1

SD PVP 1:3

PVP-K30

SD PVP 1:5

SD PEG 1:3

SD PEG 1:5

Spironolactone

PM P407 1:5

PM P407 1:3

PM P407 1:1

PM PVP 1:5

PM PVP 1:3

PM PVP 1:1

PEG-6000

PM PEG 1:1

PM PEG 1:3

PM PEG 1:5

Diffraction angel 2T ()

FormulationPhysical mixture Solid dispersion

Dissolution efficiency Percent dissolved Dissolution efficiency Percent dissolved

PM PEG 1:1 13.27 0.86b 21.55 1.33 23.97 0.57b 31.08 1.65

PM PEG 1:3 18.45 1.36b 26.57 1.54c 30.59 0.25b 39.98 2.03c

PM PEG 1:5 21.67 1.00b 28.91 2.25c 32.96 0.92b 43.24 0.95c

PM PVP 1:1 20.18 0.27 29.59 1.53 29.75 0.52b 42.67 0.65d

PM PVP 1:3 27.69 0.38c 41.30 1.33c 40.87 0.56b 55.57 1.15

PM PVP 1:5 28.97 0.95c 42.38 0.60c 32.07 0.27b 44.26 0.93d

PM P407 1:1 45.17 0.17b 52.65 1.29 57.21 0.78 67.61 0.54d

PM P407 1:3 49.48 0.31b 60.87 2.33c 62.45 1.64c 70.75 1.43

PM P407 1:5 50.33 0.24b 59.62 1.72c 63.54 1.40c 74.08 2.39d

aAt 120 min in 0.1 M HCl. Data are presented as mean standard deviation, n = 3. bANOVA indicated a significant difference (P < 0.05) among all three ratios. cANOVA indicated a significant difference among all three ratios and pair-wise comparisons (Tuckey method) indicated no significant difference for 1:3 versus 1:5. dANOVA indicated a significant difference among all three ratios and pair-wise comparisons (Tuckey method) indicated no significant difference for 1:1 versus 1:5.

Table 2Dissolution efficiency and percent spironolactone dissolved from physical mixtures and solid dispersions at 120 min in 0.1 M hydrochloric acid.

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spironolactone which suggest absence of change in the polymorph. All solid dispersions of spironolactone showed reduced intensity and broadening of spironolactone peaks suggesting conversion of crystalline spironolactone to partially disordered spironolactone molecules. PVP solid dispersions also showed elevation of baseline indicating conversion of crystalline spironolactone to completely amorphous form. Superimposable PXRD patterns of the physical mixtures and solid dispersions and absence of any new diffraction peak also ruled out the possibility of a chemical interaction.

Reduced intensity of peaks of spironolactone in all solid dispersions of spironolactone compared to their physical mixtures suggests reduced crystallinity of spironolactone. During the formulation of solid dispersions, solvent evaporation causes supersaturation of drug which if maintained by the polymer, inhibits drug crystallization either by formation of drug-polymer complex or by retardation of nucleation, the degree of which depends upon polymer concentration and its molecular weight [20, 32-35]. If the polymer concentration is high enough to inhibit crystallization of the drug during formulation, the dispersion will contain completely amorphous drug entities while at low polymer concentrations, crystallization will not be inhibited and the dispersion would contain some crystalline/partially disordered drug entities. Thus, with

increasing polymer concentration, the crystallinity of the drug reduces further. Conversion to completely amorphous state in PVP K30 solid dispersions of spironolactone suggests greater miscibility of spironolactone in the polymer and presence of some binding forces between spironolactone and PVP K30 molecules.

3.6. Fourier transform infrared spectroscopy

Fourier transform infrared (FT-IR) spectra of spironol-actone, polymers, physical mixture and solid dispersions of spironolactone are shown in Fig. 7. FT-IR spectra of spironolactone showed characteristic peaks at 1777, 1700, 1677 and 1619 cm-1 corresponding to C=O stretching of lactone ring, C=O stretching of thioacetyl group, C=O stretching of , -unsaturated ring and C=C stretching of , -unsaturated ring. PEG 6000 exhibited characteristic peaks at 2890 cm-1 due to C-H stretching, at 1116 cm-1 due to C-O stretching and at 3350 cm-1 due to O-H stretching. PVP K30 showed O-H stretch at 3482 cm-1 due to moisture absorption by the polymer. PVP has two potential hydrogen bonding sites; one is the nitrogen of pyrrolidone moiety and another is the carbonyl group of pyrrolidone moiety which exhibit characteristic peaks at 1288 cm-1 and 1682 cm-1, respectively.

FT-IR spectra of solid dispersions of spironolactone

Fig. 7. FT-IR spectra of physical mixtures and solid dispersions of spironolactone containing various concentrations of PEG 6000, PVP K30 and Poloxamer 407.

Spironolactone

PEG-6000SD PEG 1:1

SD PEG 1:3

SD PEG 1:5Poloxamer-407

PVP K30

PM PEG 1:1

4000 3200 2400 1800 1400 1000 6004000 3200 2400 1800 1400 1000 600

SD P407 1:5

SD P407 1:3

SD P407 1:1

SD PVP 1:5

SD PVP 1:3

SD PVP 1:1

PM PVP 1:1 PM 407 1:1

4000 3200 2400 1800 1400 1000 600 4000 3200 2400 1800 1400 1000 600

Wavenumber (cm-1)

T(%

)

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showed decrease in the number of peaks due to over-lapping of peaks corresponding to spironolactone and polymer. In solid dispersions with PEG 6000, some of the peaks corresponding to spironolactone disappeared due to overlapping of FT-IR spectra. In the case of PVP K30, due to steric constraints on nitrogen atom of PVP K30, the carbonyl group is more favored for hydrogen bonding. However, due to overlapping spectra of PVP K30 and spironolactone, participation of carbonyl group of PVP K30 in hydrogen bonding could not be confirmed. Nevertheless, the peak corresponding to the carbonyl group of thioacetyl group of spironolactone shifted to 1690 cm-1 from 1700 cm-1 suggesting formation of hydrogen bonding. Also, the peak corresponding to O-H stretch of PVP K30 shifted to significantly lower wavelengths. In Poloxamer 407 solid dispersions, the characteristic peaks were found at 2890, 1343 and 1107 cm-1 due to C-H stretch, in plane O-H bend and C-O stretch, respectively. The obtained spectra showed peak corresponding to C=O stretching of lactone carbonyl of spironolactone was shifted from 1777 cm-1 to 1769-1770 cm-1, and from 1126 cm-1 to 1115 cm-1 which suggests the presence of strong hydrogen bonding. The presence of hydrogen bonding in PVP K30 and Poloxamer 407 solid dispersions suggest formation of molecular dispersion rather than clusters of drug crystalline/amorphous entities. The absence of generation of new peak in any solid dispersion again confirmed absence of strong chemical interaction [7].

4. Conclusion

Solid dispersions of spironolactone with PEG 6000 improved dissolution profile while PVP K30 and Poloxamer407 enhanced solubility as well as dissolution profile. The dissolution efficiency of polymer solid dispersions of spironolactone were ranked as follows: Poloxamer 407 > PVP K30 > PEG 6000. The physical characterization by DSC, PXRD and FT-IR studies revealed that dissolution enhancement of spironolactone from solid dispersions was due to the formation of disordered structures. FT-IR studies revealed hydrogen bonding of spironolactone with PVP K30 and Poloxamer 407 indicating formation of solid solution resulting into greater dissolution efficiency than that of PEG 6000 solid dispersions.

Acknowledgments

Abstracted in part from a thesis submitted by Shreya Shah for partial fulfillment of the requirements for Masters in Science degree. The authors acknowledge St. Johns University for providing financial assistance and research facilities to carry out this research.

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