INTENSIFICATION OF THE SOLUBILITY OF BCS CLASS II DRUG ...

www.wjpps.com Vol 7, Issue 5, 2018.

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Raju. World Journal of Pharmacy and Pharmaceutical Sciences

INTENSIFICATION OF THE SOLUBILITY OF BCS CLASS II DRUG

CARVEDILOL USING SPRAY DRYING BY FORMULATING A SOLID

DISPERSION

Tina Raju*

Assistant Professor, DM WIMS College of Pharmacy, Naseera Nagar, Meppadi P. O.,

Wayanad, 673577.

ABSTRACT

Orally administered drugs completely absorb only when they show fair

solubility in gastric medium and such drugs shows good

bioavailability. The solubility and dissolution properties of drugs play

an important role in the process of formulation development. Problem

of solubility is a major challenge for formulation scientist which can be

solved by different technological approaches during the

pharmaceutical product development work. A major problem with

BCS class II drug is their low solubility in biological fluids, which

results into poor bioavailability after oral administration. Carvedilol is

a non-selective beta and alpha blocker which is insoluble in water. It is

used in the treatment of mild to severe congestive heart failure (CHF)

and high blood pressure. As the solubility is very poor the bioavailability is only 25-35%.

The problem of poor solubility can be overcome using any of the physical or chemical

methods of solubility enhancement. The purpose of this research was to improve the

solubility of Carvedilol by spray drying technique using hydrophilic polymers β-Cyclodextrin

and Plasdone-K30. Prepared solid dispersions were evaluated for drug content, saturation

solubility and in-vitro drug release study. The compatibility and surface morphology was

studied by Fourier Transforms Infrared spectroscopy (FTIR), Differential Scanning

Calorimetry (DSC) and Scanning Electron Microscopy (SEM) respectively.

KEYWORDS: Bioavailability, Carvedilol, Hypertension, PVP-K30, Solid dispersion.

WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES

SJIF Impact Factor 7.421

Volume 7, Issue 5, 1261-1281 Research Article ISSN 2278 – 4357

*Corresponding Author

Tina Raju

Assistant Professor, DM

WIMS College of

Pharmacy, Naseera Nagar,

Meppadi P. O., Wayanad,

673577.

Article Received on

06 March 2018,

Revised on 26 March 2018,

Accepted on 17 April 2018,

DOI: 10.20959/wjpps20185-11565

http://en.wikipedia.org/wiki/Congestive_heart_failure

http://en.wikipedia.org/wiki/Hypertension


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INTRODUCTION

Oral formulation has been the preferred and most common route of drug delivery around

the globe. The popularity of this dosage form is owing to its ease of administration and

good patient compliance. But for many drugs, formulation of solid dosage form can be an

inefficient mode for administration as approximately 40% or more of the NCE being

generated through drug discovery programs have problem in water-solubility. For drugs

with poor aqueous solubility, dissolution is the rate limiting step for its bioavailability.[2,5]

The therapeutic effect of drugs depends on the drug concentration at the site of action.

The absorption of the drug into the systemic circulation is a prerequisite to reach the site of

action for all drugs, except those drugs that are applied at the site of action, or

intravenously injected.[8,9,11]

In general it can be stated that the rate of absorption, therefore,

onset and extent of the clinical effect, is determined by the dissolution of the drug and the

subsequent transport through the biological membrane. Therefore, together with the

permeability, the solubility and dissolution property of a drug are key determinants of its

oral bioavailability.[1,3]

The process of „Solubilization‟ involves the breaking of inter-ionic or intermolecular bonds in

the solute, the separation of the molecules of the solvent to provide space in the solvent for

the solute, interaction between the solvent and the solute molecule or ion.[12,14]

The

formulation of hydrophobic drugs as solid dispersions is a significant area of research

aimed at improving the dissolution and bioavailability of hydrophobic drugs.[5,8]

Solid

dispersions consisting of two components in the solid state are referred to as binary systems.

The two components are a water-soluble carrier and a hydrophobic drug dispersed in the

carrier substance.[5]

Chiou and Riegelman defined the term solid dispersion as „the dispersion of one or more

active ingredients in an inert carrier matrix at solid-state prepared by the melting (fusion),

solvent or melting- solvent method. On the other hand, Corrigan suggested the definition as

„product formed by converting a fluid drug-carrier combination to the solid state‟. Spray

drying can be used to formulate solid dispersion of a hydrophobic drug using the principle of

solvent evaporation in which atomization of a solution of one or more solids via a nozzle,

spinning disk or other device followed by evaporation of the solvent from the droplets takes

place.[25,26]


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MATERIALS AND METHODS

Carvedilol was supplied as a gift sample by Mylan Laboratories, Bangalore. β-Cyclodextrin,

Plasdone K-30 and Methanol were provided by Research Lab Fine Chem. Industries,

Mumbai. The Spray Dryer of model Labultima LU222 Advanced was used for preparing

solid dispersion.

1.0 METHODS

1.0.1 Characterization of drug

1. Organoleptic properties

The sample of Carvedilol was analyzed for its colour, odour and physical appearance.

2. Determination of Melting Point

Melting point of Carvedilol was determined by open capillary method using Thiel‟s tube.

Average of triplicate readings was taken, and compared with literature.

1.0.2 Spectroscopic analysis

1. Determination of λmax

Carvedilol (10mg) was dissolved in 10ml of methanol to obtain the stock solution of

concentration 100μg/ml. From this stock solution, 1 ml was withdrawn and diluted to 10ml to

obtain solution of 10μg/ml. Absorbance was checked using UV-spectrophotometer in the

wavelength range of 200-400nm.

2. Preparation of calibration curve for Carvedilol

Stock solution of 100μg/ml was prepared by dissolving 10mg pure drug into 10ml methanol.

The further dilutions (2-16μg/ml) were prepared using methanol. Absorbance were recorded

at 241nm using UV-Spectrophotometer, standard curve was plotted and values of slope,

intercept and coefficient of correlation were calculated.

3. Determination of saturation solubility of Carvedilol

Solubility of Carvedilol was determined in solution of distilled water, 0.1N HCl (pH 1.2) and

phosphate buffer (pH 6.8). Initially, excess amount of Carvedilol was added to 10ml each of

the above solutions in 10ml volumetric flask. Then these volumetric flasks were shaken using

mechanical shaker for 24hours. The samples were then filtered, diluted suitably and analyzed

spectrophotometrically at 241nm. Triplicate reading were taken.


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1.0.3 Compatibility study between drug and excipients

1. FTIR spectroscopic study of drug and polymers

The infrared absorption spectrum of pure Carvedilol, Plasdone K-30, β-cyclodextrin, and the

physical mixture of carvedilol with the polymers Plasdone K-30, β-cyclodextrin were

recorded on FTIR spectrophotometer for evaluating the chemical compatibility of Carvedilol

with the hydrophilic polymers. The spectra were taken after preparing the pellet using 2-4mg

of sample with potassium bromide as a reference compound and the sample was scanned

under IR radiation from 4000-400cm-1

.

2. Differential Scanning Calorimetry (DSC) study of drug

DSC was performed in order to assess the thermotropic properties and thermal behaviour of

the drug (Carvedilol) and the prepared solid dispersion. Samples were sealed in an aluminium

pan and heated at the rate of 100C/min from 30

0C-300

0C under nitrogen atmosphere with

flow rate of 10ml/min. Thermograms of pure Carvedilol and optimized batch of solid

dispersion were recorded using METTLER DSC 30S, Mettler Toledo India Pvt. Ltd.

instrument equipped with an intracooler.

3. Powder X -Ray diffraction (PXRD) study of drug

Powder X-ray diffraction patterns were recorded for the pure Carvedilol to determine its

crystalline nature using Brucker D2 Phaser X-diffractometer.

1.1 EXPERIMENTAL WORK

1.1.1 Formulation of Solid Dispersion using Spray Drying Technique

1) Composition of solid dispersion of Carvedilol

Solid dispersions of Carvedilol with β-cyclodextrin and Plasdone K-30 were prepared at three

drug:polymer molar ratios, 1:1, 1:2 and 1:3 using spray drying technique. The formulation

table is shown in table no.1.

Table No.1: Formulation Table for preparing solid dispersion.

Batch Code Carvedilol(gm) β-cyclodextrin(gm) Plasdone K-

30(gm)

SD1 1 1 -

SD2 1 2 -

SD3 1 3 -

SD4 1 - 1

SD5 1 - 2

SD6 1 - 3


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2) Formulation of solid dispersion using Spray Drying

Carvedilol solid dispersions were prepared by solvent evaporation method using carriers (β-

cyclodextrin and Plasdone K-30) in proportions viz. 1:1, 1:2 and 1:3 (drug : carrier). The drug

and carrier were dissolved in methanol (100ml). The solvent was evaporated by spray drying

process, which was carried out using laboratory scale spray dryer. The parameters of spray

drying were set as shown in Table no.2. The powder was stored in desiccators until further

evaluation.

Table No.2: Spray Drying Parameters.

Sr. No. Parameters Values

1 Inlet Temperature 350C

2 Outlet Temperature 350 C

3 Cool Temperature 500 C

4 Inlet high 500 C

5 Outlet high 400 C

6 Aspiratory Flow Rate 40 Nm2/hr

7 Feed Pump Flow Rate 2 ml/min

8 D-Block on 1 second

9 D-Block off 60 second

10 Data Log Interval 60 second

1.1.2 Characterization of Solid Dispersion

1) Determination of Percentage yield

The yield of the final solid dispersion of all ratios was calculated by using the final weight of

solid dispersion after drying and the initial weight of drug and polymer used for preparation

of solid dispersion. The following formula is used for calculation of percent practical yield-

2) Determination of drug content of prepared solid dispersions

The percentage drug content in solid dispersion was estimated by dissolving quantities

equivalent to 10mg of solid dispersion in 10ml methanol, centrifuged for 10min and filtered

through 0.45μm membrane filter, appropriately diluted with distilled water and the UV

absorbance were recorded at 241nm by using UV-visible spectrophotometer. The percentage

drug content was calculated using the following formula.


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3) Determination of saturation solubility of prepared solid dispersions

Excess amount of solid dispersions were added to 250ml conical flasks containing 25ml of

distilled water. The sealed flasks were shaken for 24hrs at 37±0.5ºC. Then aliquots were

filtered through Whatmann filter paper. The concentration of Carvedilol was determined by

UV spectrophotometer at 241nm. Saturation solubility study was also performed in 1.2pH

phosphate buffer and 6.8pH buffers.

4) FTIR study of solid dispersion

Infrared spectra of solid dispersion powder was obtained using FTIR spectrometer in the

range of 4000-400cm-1

. This was done to study about the compatibility between drug and

polymers in the solid dispersion.

5) Differential Scanning Calorimetry (DSC) study of solid dispersion

DSC was performed to characterize thermal changes in the melting behavior of Carvedilol

with polymers present in solid dispersion. DSC study also reveals whether the drug is in

crystalline or in amorphous form. The study of prepared solid dispersion were carried out

using thermal analyzer. DSC studies were carried out using thermal analyzer (TA SDT-

2790). The samples were hermetically sealed in an aluminum pan and heated at constant rate

of 100C/min over a temperature range of 30-300

0C. Inert atmosphere was maintained by

purging nitrogen gas at a flow of 10ml/min.

6) Scanning Electron Microscopy (SEM) study of solid dispersion

SEM of optimized solid dispersion batch was carried out using JSM 6360, JEOL India Pvt.

Ltd. to study the morphological characteristics of the solid dispersion.

7) In-vitro dissolution studies of Carvedilol solid dispersion systems

Dissolution study under gastric conditions, intended to select the solid dispersion system with

superior dissolution properties to be incorporated into the formulation of immediate release

tablet, were performed using the USP dissolution apparatus II at 50 rpm. A sample equivalent

to 12.5mg of Carvedilol was placed in the dissolution vessel containing 900ml of 0.1N HCl

maintained at 37±0.50C. At appropriate intervals, samples from the dissolution medium

werewithdrawn, filtered, and concentrations of Carvedilol were determined

spectrophotometrically at 241nm. The dissolution studies were conducted in triplicate and the

cumulative % drug release was plotted against time.


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RESULTS AND DISCUSSION

1.1 AUTHENTICATION OF DRUG

1. Organoleptic Properties

Carvedilol is a white, odourless, bitter fine crystalline powder.

2. Melting point of Carvedilol

The temperature at which solid drug changes into liquid was noted as the melting point of the

Carvedilol. It was found to be 114-1160C. (Std. - 116-118

0C).

1.2 SPECTROSCOPIC ANALYSIS

1.2.1 Determination of λmax of Carvedilol

The standard solution of Carvedilol of concentration 10µg/ml showed maximum

absorbance at the wavelength of 241nm. Hence the λmax of Carvedilol was found to be

241nm.

Fig. 1: λmax of Carvedilol.

1.2.2 Plotting of Calibration curve for Carvedilol

Calibration curve of Carvedilol in 0.1 N HCl (pH 1.2) showed straight line which passes from

origin. The Beer‟s Lambert‟s law was found to be obeyed over the range of 2-16μg/ml.


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Table No.3: Data for calibration curve of Carvedilol in 0.1 N HCl

Concentration

(μg/ml) Absorbance*

0 0.0000±0.012

2 0.0875±0.011

4 0.1874±0.013

6 0.2515±0.011

8 0.3581±0.013

10 0.4312±0.014

12 0.4962±0.012

14 0.5681±0.013

16 0.6620±0.013

*All values are expressed as mean ± SD (n=3)

Fig. 2: Calibration curve of Carvedilol in 0.1N HCl (pH 1.2).

The details of calibration curve are as given below

Equation is, y = mx+c

Where, y =absorbance, m = slope, x = concentration and c = intercept

From the calibration curve equation obtained was.

y= 0.040x+0.012.

Table No.4: Values obtained from standard calibration curve of Carvedilol

Regression

Coefficient (R2)

0.997

Slope(m) 0.040

Intercept(c) 0.012

1.2.3 Saturation solubility of Carvedilol

Solubility of Carvedilol was determined in solution of 0.1N HCl (pH 1.2), distilled water and

phosphate buffer (pH 6.8).


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Table No.5: Saturation solubility of Carvedilol in different solvents

Solvent Saturation Solubility

( mg/ml)*

Distilled Water 0.0044±0.3

0.1N HCl(pH 1.2) 0.7642±0.2

pH 6.8 phosphate buffer 0.5491±0.3


1.3 COMPATIBILITY STUDY BETWEEN DRUG AND EXCIPIENTS

1.3.1 FTIR spectra of Carvedilol

Fig.3 shows the typical Fourier transform-infrared (FTIR) spectrum of Carvedilol in the

range of 4000 to 400cm−1

.

Fig. 3: FTIR Spectrum of Carvedilol.

Table no.6: Interpretation of FTIR spectra of Carvedilol.

Sr. No. Peak position Functional Group

1 3408.57cm-1

N-H and O-H stretching

2 2360.44cm-1

C-H stretching

3 1603.52cm-1

N-H bending

4 1347.03cm-1

O-H bending

The IR spectrum of pure carvedilol showed the peak at 3408.57cm–1

which corresponds to N-

H stretching. The hetero-aromatic structure shows the presence of the C-H stretching

vibrations in the region 2360.44cm–1

. The bands corresponding to the in-plane C-H

deformations are observed in the regions 1,000 to 1,300cm−1

. The bands are sharp but of

weak to minimum intensity. A medium experimental peak around 1252 to 1402cm−1

in the

FT-IR was assigned to the C-C stretching vibrations. The bands in the regions 1502 to

1603.52cm−1

observed in both FTIR were assigned to the C = C stretching vibrations.


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1.3.2 FTIR spectra of β-cyclodextrin

Fig. 4: FTIR spectra of β-cyclodextrin.

The IR spectra of β-cyclodextrin shows a broad band at 3381.57cm-1

, which is caused by the

valence vibrations of the O-H bonds in the primary hydroxyl groups (C – 6 - OH) connected

by the intermolecular hydrogen bonds or in the secondary hydroxyl groups connected by the

intramolecular hydrogen bonds (the C – 2 - OH group of one glucopyranose unit and C – 3 -

OH group of the adjacent glucopyranose unit). Also, in the IR spectrum of β-CD the

absorption band with maximum at 2919.7cm-1

is observed. It belongs to the valence

vibrations of the C-H bonds in the CH and CH2 groups. In the region 1400 - 1200cm-1

the

absorption bands of the deformation vibrations of the С-Н bonds in the primary and

secondary hydroxyl groups of β-CD (1384.64cm-1

) and in the interval 1200-1030сm-1

the

absorption bands of the valence vibrations of the С-О bonds in the ether and hydroxyl groups

of β-CD (1157.06 and 1029.8cm-1

) are registered. The absorption bands in the region 950 -

700cm-1

belongs to the deformation vibrations of the С-Н bonds and the pulsation vibrations

in glucopyranose cycle present in β-cyclodextrin structure.

1.3.3 FTIR spectra of Plasdone K-30-

Fig. 5: FTIR spectra of Plasdone K-30.


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A broad band at 2360.44cm−1

in the spectrum of Plasdone K-30 shows the C-H stretching

vibrations, and the vibration band of C=O group appears at 1630.52cm−1

suggesting some H-

bonding carbonyl groups exist in Plasdone K-30. The characteristic C-N stretching vibration

is observed at 1384.64cm-1

.

1.3.4 FTIR spectra of Carvedilol with β-cyclodextrin

Fig. 6: FTIR spectra of Carvedilol with β-cyclodextrin.

Inclusion complex formation may be confirmed by IR spectroscopy because bands resulting

from the included “guest” molecule are generally shifted or their intensities are altered. The

broadening of the peak may be due to the inter-molecular H-bonding between the OH groups

of Carvedilol and β-cyclodextrin during the inclusion complex formation. Also, no significant

change in the characteristic peaks present in the pure drug were observed which shows that β-

cyclodextrin is compatible with Carvedilol.

1.3.5 FTIR spectra of Carvedilol with Plasdone K-30

Fig. 7: FTIR spectra of Carvedilol with Plasdone K-30.


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The results revealed no considerable changes in the IR peaks of Carvedilol, when mixed with

polymer Plasdone K-30. These observations indicated the compatibility of Plasdone K-30

with Carvedilol. IR spectra indicated no well-defined interaction between the drug and

polymer.

1.3.6 DSC study of Carvedilol

DSC enables the quantitative detection of all processes in which energy is required or

produced (i.e., endothermic or exothermic phase transformations). The thermal analysis of a

compound utilizing DSC, usually offers information about several physicochemical

properties such as crystalline nature and thermal stability of the investigated compound.

The DSC curve of Carvedilol showed a sharp endothermic peak (Tpeak = 117.65°C)

corresponding to its melting point which indicates its crystalline nature (Fig.8).

Fig. 8: DSC curve of Carvedilol.

1.3.7 Powder X - Ray diffraction (PXRD) study of Carvedilol

The X-ray diffractogram of Carvedilol was characterized by the presence of sharp peaks

indicative of the crystalline nature of drug (fig. 9).


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Fig. 9: PXRD curve of Carvedilol

1.4 CHARACTERIZATION OF SOLID DISPERSIONS

1.4.1 Percentage Practical Yield

The results of percent practical yield studies are shown in Table no.7. The % Practical yield

of the prepared solid dispersions by spray dryer method was found to be maximum for batch

SD4 (69.73%).

Table No.7: Percentage practical yield of various batches of solid dispersion

Sr. No. Batch code Percentage Yield

1 SD1 62.85%

2 SD2 57.49%

3 SD3 65.28%

4 SD4 69.73%

5 SD5 65.71%

6 SD6 59.14%

1.4.2 Drug content of solid dispersions

The drug content in the spray dried solid dispersion was found to be 66.87 to 87.53%

suggesting that the spray drying process was successful in achieving good encapsulation of

the drug. Percent drug content of Carvedilol in spray dried solid dispersions was found to be

increased with increase in the concentration of hydrophilic carriers. The batch SD6 with

drug:carrier ( Carvedilol: Plasdone K30) ratio of 1:3 showed high drug content. Hence this

batch can be incorporated into tablet formulation. The percent drug content values of

Carvedilol in different solid dispersion batches are shown in Table no.8.


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Table No.8: Drug content of solid dispersion.

Sr. No. Batch code % drug content

1 SD1 66.87%

2 SD2 82.61%

3 SD3 84.42%

4 SD4 72.38%

5 SD5 79.96%

6 SD6 87.53%

1.4.3 Saturation solubility of solid dispersions in various solvents

The solubility of spray dried solid dispersions of Carvedilol in distilled water, 0.1N HCl (pH

1.2) and in phosphate buffer (pH 6.8) was determined so as to select an appropriate batch of

solid dispersion for further formulation of tablets.

The increase in solubility was found to be linear with respect to the increase in the

concentration of carrier. The batch SD6 with drug to Plasdone K-30 ratio of 1:3 showed

greater increase in the solubility as compared to β-cyclodextrin. This is due to the greater

hydrophilicity of Plasdone K30 than β-cyclodextrin. PVP polymers cause a reduction in the

interfacial tension between the drug and the dissolving solution. Moreover, it was suggested

that Plasdone K30 might form soluble complexes with the drug. Also the wettability and

porosity of the particles was also increased. The results of solubility study of solid dispersion

of Carvedilol are tabulated in Table no.9.

Table No.9: Saturation Solubility of various batches of solid dispersion.

Batch

Code Polymer

Drug:Polymer

ratio

Solvents

Distilled

water*

0.1N HCl

(pH 1.2)*

Phosphate

buffer

(pH 6.8)*

SD1 β-

cyclodextrin

1:1 0.3854±0.2 0.8754±0.3 0.6749±0.4

SD2 1:2 0.6749±0.2 0.9916±0.2 0.8443±0.1

SD3 1:3 0.8357±0.4 1.2837±0.4 1.3786±0.1

SD4 Plasdone

K-30

1:1 0.3774±0.3 1.8412±0.3 0.7692±0.2

SD5 1:2 0.8576±0.4 2.6348±0.4 1.0428±0.3

SD6 1:3 1.1729±0.4 4.1587±0.2 1.4287±0.2


1.4.4 In-vitro drug release study of solid dispersion

The dissolution profiles of solid dispersion batches are shown in (Table no.10). It was evident

that the pure drug exhibited a slow dissolution even after 60 minutes where the percentage of

drug dissolved after 60minutes only reached about 18.58±0.02%. This is due to the


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hydrophobicity, poor wettability and/or agglomeration of Carvedilol particles resulting into

hindering its dissolution. All solid dispersions showed enhanced dissolution rate compared to

pure Carvedilol that might be due to the effect of hydrophilic carriers on drug wettability and

dispersibility. These results could be attributed to the general phenomenon of particle size

reduction of Carvedilol particle during the spray drying operation. Also, solubilisation,

molecular/colloidal dispersion of drug in the mixture and reduction in the drug crystallinity

(i.e. polymorphic transformation of drug crystals) that were obtained via the formulation of

solid dispersions using spray dryer could have contributed to the increase in solubility.

The batch SD6 with Carvedilol to Plasdone K-30 ratio of 1:3 showed the maximum drug

release as compared to the other batches. The drug release profile of the solid dispersion

batches is shown in fig.10 and 11.

Table No.10: Cumulative % drug release data of Solid dispersion batches.

Sr.

No Time (min)

% Cumulative drug release*

Pure drug SD1 SD2 SD3 SD4 SD5 SD6

1 0 0.00±0.00 0.00±0.00 0.00±0.00 0.00±0.00 0.00±0.00 0.00±0.00 0.00±0.00

2 10 3.31±0.03 12.45±0.05 19.34±0.06 26.47±0.05 32.67±0.03 39.57±0.03 43.56±0.03

3 20 5.73±0.01 33.48±0.06 39.37±0.03 37.46±0.02 48.29±0.01 47.67±0.03 58.26±0.02

4 30 8.06±0.03 48.87±0.05 46.35±0.02 52.67±0.03 54.42±0.03 59.34±0.01 69.41±0.06

5 40 11.41±0.02 66.48±0.04 59.14±0.03 68.77±0.03 63.97±0.03 69.44±0.02 84.19±0.03

6 50 13.67±0.02 75.95±0.06 76.73±0.03 80.91±0.01 71.26±0.01 76.99±0.01 89.61±0.04

7. 60 18.58±0.02 79.37±0.04 81.16±0.01 88.38±0.03 78.96±0.03 89.76±0.03 93.39±0.06


Fig. 10: Cumulative drug release profile of pure drug,SD1,SD2 and SD3.


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Fig. 11: Cumulative drug release profile of pure drug,SD4,SD5 and SD6.

1.4.5 FTIR Spectra of optimized solid dispersion batch (SD6)

Fig. 12: FTIR spectra of batch SD6.

The effect of the polymer Plasdone K-30 on Carvedilol was studied through interaction

studies. The IR spectra of the optimized batch SD6 was scanned in the range of 4000-400cm-

1. If the drug and the polymer would interact, then the functional groups in the FTIR spectra

would show band shifts and broadening compared to the spectra for the pure drug and

polymer. The FTIR spectra obtained from solid dispersions showed peaks which were a

summation of the characteristic peaks obtained with the pure drug and pure carriers and

spectra‟s can be simply regarded as the superposition of those of Carvedilol and carriers. This

showed that there was no chemical interaction of the drug with carriers even in the

amorphous state when the granules were prepared by the solid dispersion method. An


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increase in the polymer content also did not initiate any drug polymer interactions. FTIR

spectra‟s is shown in Fig.12.

From the IR spectra it was found that there was no significant change observed in the

characteristic peaks of the drug which shows that there is no interaction occuring in between

Carvedilol and Plasdone K-30. Also it can be concluded that there was no effect of the spray

drying process on the drug.

1.4.6 DSC study of optimized solid dispersion batch (SD6)

The DSC thermogram of solid dispersion showed a disappearance of the endothermic peak

which was observed in the DSC curve for pure Carvedilol and also there was change in the

peak intensity. The absence of endothermic peak might be due to the formation of solid

dispersion of the drug in the presence of hydrophillic polymer where the crystalline drug

could be transformed into an amorphous state. This amorphousness might be related to the

intermolecular hydrogen bonding and complexation between drug and Plasdone K30,

respectively. The thermogram of spray dried particles of Carvedilol showed change in the

melting point which is shown as a broad peak at 950C. Such change in the melting point

indicates changes in the crystalline state of Carvedilol after spray drying process. Also, the

melting temperature of solid dispersion decreases with decreasing their particle size. The

melting temperature increases as the particle size increases. Thus, as the particle size

decreases surface area-to-volume ratio of the particle increases. The larger surface area

allows a greater interaction with the solvent and ultimately enhances the solubility of the

drug.

Fig. 13: DSC curve of batch SD6.


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1.4.7 Scanning Electron Microscopy (SEM) of solid dispersion batch SD6

SEM images of the prepared Carvedilol solid dispersion is shown in Fig.14. The particles of

the solid dispersion were found to be spherical in shape. The particle size of the spray dried

particles is also decreased. This is essential to enhance the solubility. SEM showed smooth

surface of Carvedilol solid dispersion particles with greater number of pores which indicated

that there is increase in the porosity and hence the dissolution rate of these particles was also

increased. This shows that transformation of the crystalline drug into amorphous state has

occured with enhanced solubilization and dissolution rate of the spray dried particles.

Fig. 14: SEM images of Solid dispersion batch SD6.

CONCLUSION

The main objective of this study was to increase the solubility of Carvedilol using

hydrophillic polymers β-cyclodextrin and Plasdone K-30. Further the incorporation of the

prepared solid dispersion was done in the formulation of press-coated pulsatile drug delivery

system for the treatment of hypertension. The results of saturation solubility, drug content

and in-vitro dissolution study of solid dispersions of Carvedilol indicated that the solubility of

Carvedilol was increased with increasing the concentration of hydrophillic polymers.

The batch SD6 with drug to Plasdone K-30 ratio of 1:3 showed the greater increase in

solubility than the pure drug. The FTIR spectroscopy study showed that there was no

interaction between Carvedilol, β-cyclodextrin and Plasdone K-30. The DSC study of the

pure drug showed melting endotherm at 1180C corresponding to the melting point of the drug

indicating that the drug is crystalline. Whereas the DSC study of solid dispersion indicated


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that the drug is in amorphous state. Thus it can be concluded that spray drying is effective in

increasing the solubility of Carvedilol. Further the results of SEM study showed that the

spray dried solid dispersion particles of batch SD6 are spherical in shape with greater

porosity. This indicates that the solubility was increased which is further confirmed from the

in-vitro dissolution studies.

ACKNOWLEDGEMENT

My heartiest thanks go to my beloved and respected guide Mr. M.A.Bhutkar, Associate

professsor, Department of Pharmaceutics, Rajarambapu College of Pharmacy, Kasegaon, for

his excellent guidance, valuable suggestions, moral support and constant inspiration during

this endaevour. Next with pride and elation I would like to give my humble thanks to my

esteemed teacher respected Dr.C.S.Magdum, Principal, Dr. S.K. Mohite, Vice-Principal and

Head of Department of Pharmaceutical Chemistry, and Dr. M. N. Nitalikar, Associate

professor, Department of Pharmaceutics, Rajarambapu College of Pharmacy, Kasegaon, for

providing the necessary infrastructure and all the facilities required to carry out my research

work.

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