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October - December 2019 2 Journal of Pharmacy and Chemistry • Vol.13 • Issue.4

Online : ISSN 2349-669X

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Volume 13 • Issue 4 • October – December 2019

CONTENTS

Synthesis, Characterization and Pharmacological Evaluation of Novel Quinoline Derivatives ....................................... 3

S. CHAND BASHA, C. SURYA SAVARNY, V. SREENIVASULU,

K. RAJESH BABU AND K. AHAMED BASHA

Zero Order Spectrophotometric Method Development and Validation

for Estimation of Cadexomer Iodine in Dosage Form .................................................................................................... 8

MAHESH.M, S.SREE VIDYA, MANAMASA AJAY,

KOLAR IRSHAD BASHA AND MANYAM VAMSIKRISHNA

Analytical Method Development and Validation of Venlafaxine

Hydrochloride Assay by RP-HPLC in Bulk and Pharmaceutical Dosage Form .............................................................. 12

K.S.NATARAJ, A. SRINIVASA RAO AND R.SURYA SANTHOSH

Enhancement of Solubility by Solid dispersion Technique – A Review ........................................................................ 19

LUBNA NOUSHEEN1, S. RAJASEKARAN, MOHD. SHOUKHATULLA ANSARI

Instruction to Authors

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mailto:[email protected]




Synthesis, Characterization and Pharmacological Evaluation of Novel

Quinoline Derivatives

S. CHAND BASHA1*, C. SURYA SAVARNY1, V. SREENIVASULU2,

K. RAJESH BABU1 AND K. AHAMED BASHA1

1 Department of Pharmaceutical Chemistry, Annamacharya college of Pharmacy, Rajampet, India.

b Professor, Sri Krishna Chaitanya College of Pharmacy, Madanapalle-517325, Chittoor District, Andhra Pradesh, India.

ABSTRACT

A novel series of 6-chloro-1, 4-dihydro-2-diphenylquinoline-4-carbohydrazide derivatives were syn-

thesized by means of nucleophilic displacement with aromatic aldehydes. The title analogs were sub-

sequently characterized by FT-IR, NMR and MS spectral analysis and subjected to screening against

chloroquine sensitive JSB strains of plasmodium falciparum (RPMI-1640) in 96 well microtitre plates.

However, over 6 novel quinoline derivatives three with electro withdrawing group exhibits mild to

moderate anti malarial activity with respect to chloroquine as reference standard.

Keywords: Quinoline, nucleophilic substitution, FT-IR, NMR, MS and Plasmodium falciparum.

INTRODUCTION

Malaria remains a very serious problem in large parts of the

world and places a heavy social burden particularly on de-

veloping countries. The disease is endemic in 108 countries

and every year 250 million clinical cases and nearly 1 million

deaths are recorded. Malaria parasite have developed resis-

tance against many of the available drugs[1], this mounting

threat of malarial resistance has heightened the urgency to

discover and develop anti effective agents with novel mech-

anism of action and enhanced activity profile that are able to

circumvent resistance. To overcome the clinical limitations

of most recently used potent anti malarial drugs, consider-

able research effects have been directed to the discovery of

novel hetero cyclic quinolines with high potency local anti-

malarial activity with reduced systemic adverse effects [2].

Quinoline, a heterocyclic aromatic compound consist of

benzene ring attached to pyridine[3] which consists ‘N’

nitrogen as a hetero atom with huge complex derivatives

lead to many advances in heterocyclic chemistry[4]. These

were versatile synthetic heterocyclic compounds with vari-

ous considerable biological activities like cardio vascular

activity, mycobacterial activity, epilepsy, CNS effects and

alzheimer’s diseases [5, 6]. In the view of these observa-

tions, the present study aims synthesis of novel Quinoline

derivatives in a simple 2 step process in which primarily

Quinoline 4-carboxylic acid derivatives were formed upon

nucleophilic substitution reactions with phenyl hydrazine

leads to formation of some new derivatives of quinolines.

MATERIALS AND METHODS

All the commercially available solvents and reagents were

of AR grade which were procured from Merck (Germany),

Correspondance E-mail: [email protected]

Sigma Aldrich chemicals Co. (Germany) and SD fine chem-

icals (Mumbai) and used without further purification. The

melting points were determined in open capillaries on a Heco

melting point apparatus and were uncorrected. The purity of

the compounds were assessed by thin layer chromatography

(TLC) on silica gel using the developing system chloroform

and ethanol in 8:2 ratio and the spots were detected by UV

radiation using UV radiation chamber. The chemical struc-

tures were confirmed by spectral analysis. FT-IR was taken

on Shimadzu 8400 spectrophotometer. 1H- NMR spectra

were recorded on 200 MHZFX 909 JOEL spectrophotom-

eter in DMSO using TMS as internal standard. Mass spectra

were obtained on JOEL-D-3000 spectrometer equipped with

atmospheric pressure chemical ionization (APCI) source.

EXPERIMENTAL WORK

The desired compounds were synthesized by the synthetic

protocols as outlined in scheme 1 respectively. The titled

synthetic work involves the following steps;

General method for the synthesis of title compounds

STEP-1

Synthesis of 6-chloro-1,4-dihydro-2-phenyl quinoline- 4-

carboxylic acid:

Take 1.1g of sodium pyruvate and 1.2g of 4-chloro aniline in

a round bottomed flask. To this mixture add 1.07g of benz-

aldehyde. The mixture is dissolved in ethanol and kept re-

flux for 3 hours. The product was collected by filtration and

re-crystallization was done by using ethanol to get a crude

product. Then the product was dried under vacuum for char-

acterization with careful operation to avoid the destruction

of 1-D structure.



N H

R

STEP – 2

Synthesis of 6-chloro-1, 4-dihydro-N, 2-diphenyl quino-

line-4-carbohydrazide:

0.01M of 6-chloro-1, 4-dihydro-2-phenylquinoline -4-car-

boxylic acid was taken into 100ml round bottomed flask.

Then 0.01M of phenyl hydrazine was dissolved in ethanol

and this mixture was poured into above round bottomed

flask. The reaction mixture was refluxed for 10 hours.

The obtained product was cooled at room temperature and

poured in ice cold water. Then filter the product and dried at

room temperature. Re-crystallization with ethanol.

General procedure for synthesis of novel quinoline deriva-

tives QC 1-6

These derivatives were synthesized according to the pro-

cedure mentioned in scheme 1 by using different aromatic

aldehydes. Finally the obtained reaction mixture was poured

into crystal ice. The solid separate out was filtered, washed

and recrystalized with ethanol to yield QC 1-6.

i. 6-chloro-1,4-dihydro-2-(2-hydroxyphenyl)-N’-

phenylquinoline-4-carbohydrazide (QC-1)

A yellow colored solid characterized by the following

physicochemical properties of % yield: 63, mp: 130-132 ºC;

FTIR (KBr) cm-1: 3316 (N-H Stretch), 2976 (C-H Stretch),

1601 (C-C in ring bend), 1301 (C-O bend); 1 H-NMR (200

MHz, DMSO): δ 4.0-6.0 (Imino proton), δ 6.34-6.81 (Quin-

oline), δ 6.66-7.18 (Phenyl hydrazine), δ 6.77-7.5 multiplet;

Mass: 390.55 (Base peak) of C21H18N3O2Cl.

Synthetic scheme of novel quinoline derivatives

The schematic representation as follows

Step: 1 O Na+

O-

H2N Cl

O

SODIUM PYRUVATE

4-CHLORO ANILINE

AROMATIC ALDEHYDE

cyclo addition

reflux for 3 hours in ethanol

COOH

Cl

6-chloro-1,4-dihydro-2-phenylquinoline-4-carboxylic acid

STEP-2

COOH

Cl

Nucleophilic

substitution

H2N

HN

6-chloro-1,4-dihydro-2-phenylquinoline-4-

carboxylic acid

Phenyl hydrazine

R = H

2-OH

2-CHO

2-Cl

4-Br

3- OCH3

4- OH

Cl

6-chloro-1,4-dihydro-N',2-diphenylquinoline-4-carbohydrazide

O

NH NH C

N H

R

O R

N H

R


ii. 6-chloro-1, 4-dihydro-2-(3-hydroxy-

4-methoxyphenyl)-N’-phenylquinoline-4-carbohydra-

zide (QC-2)

A brown colored solid characterized by the following physi-

cochemical properties of % yield: 60, mp: 132-133 ºC; FTIR

(KBr) cm-1: 3285 (N-H Stretch), 3030(C-H Stretch), 2561

(O-H stretch.), 1709 (C=O stretch); 1 H-NMR (200 MHz,

DMSO): δ 4.0-6.0 (Imino proton), δ 6.34-6.81 (Quinoline),

δ 6.66-7.18 (Phenyl hydrazine), δ 6.77-7.5 multiplet; Mass:

420.66 (Base peak) of C22H20N3O3Cl.

iii. 6-chloro-1,4-dihydro-2-(3-methoxyphenyl)-N’-

phenylquinoline-4-carbohydrazide (QC-3)

A yellow colored solid characterized by the following

physicochemical properties of % yield: 30, mp: 100-102

ºC; FTIR (KBr) cm-1: 3404 (O-H Stretch, H bonded), 3030

(C-H Stretch), 1632 (N-H bend), 1712 (C=O stretch); 1 H-

NMR (200 MHz, DMSO): δ 4.0-6.0 (Imino proton), δ 6.34-

6.81 (Quinoline), δ 6.66-7.18 (Phenyl hydrazine), δ 6.77-7.5

multiplet; Mass: 407.15 (Base peak) of C22H19N3O2Cl.

iv. 6-chloro-1, 4-dihydro-2-(3,4-dimethoxy phenyl)-N’-

phenyl quinoline-4-carbohydrazide (QC-4)

A cream colored solid characterized by the following

physicochemical properties of % yield: 32, mp: 102-103

ºC; FTIR (KBr) cm-1: 3403 (O-H Stretch, H bonded), 3027

(C-H Stretch), 1632 (N-H bend), 834 (C-Cl bend); 1 H-

NMR (200 MHz, DMSO): δ 4.0-6.0 (Imino proton), δ 6.34-

6.81 (Quinoline), δ 6.66-7.18 (Phenyl hydrazine), δ 6.77-7.5

multiplet; Mass: 434.90 (Base peak) of C23H23N3O2Cl.

v. 6-chloro-2-(4-chlorophenyl)-1,4-dihydro-N’-phenyl

quinoline-4-carbohydrazide (QC-5)

A brown colored solid characterized by the following

physicochemical properties of % yield: 55, mp: 140-141 ºC;

FTIR (KBr) cm-1: 3311 (O-H Stretch), 1596 (N-H bend),

1488 (C-C bend), 822 (C-Cl bend); 1 H-NMR (200 MHz,

DMSO): δ 4.0-6.0 (Imino proton), δ 6.34-6.81 (Quinoline),

δ 6.66-7.18 (Phenyl hydrazine), δ 6.77-7.5 multiplet; Mass:

411.52 (M+H peak) of C21H17N3OCl2.

vi. 6-chloro-1,4-dihydroN’,2-diphenyl quinoline-4-car-

bohydrazide (QC-6)

A brown colored solid characterized by the follow-

ing physicochemical properties of % yield: 82.3, mp: 135-

136 ºC; FTIR (KBr) cm-1: 3309 (O-H Stretch), 3066 (C-H

stretch), 1022 (C-O stretch), 821 (C-Cl bend); 1 H-NMR

(200 MHz, DMSO): δ 4.0-6.0 (Imino proton), δ 6.34-6.81

(Quinoline), δ 6.66-7.18 (Phenyl hydrazine), δ 6.77-7.5

multiplet; Mass: 376.05 (M+H peak) of C21H17N3OCl.

Preparation of parasites

The chloroquine sensitive JSB strains of Plasmodium

falciparum were routinely maintained in stock cultures in

medium RPMI-1640 supplemented with 25 mmol HEPES,

1% D-glucose, 0.23% sodium bicarbonate and 10% heat in-

activated human serum. The asynchronous parasites of plas-

modium falciparum were synchronized after 5% D-sorbitol

treatment to obtain only the ring stage parasitized cells [7].

For carrying out the assay, the initial ring stage parasitaemia

of 0.8-1.5% at 3% hematocrit in total volume of 200 µl of

medium RPMI-1640 was uniformly maintained.

In-vitro anti plasmodic activity testing

The in-vitro anti malarial assay was carried out in 96

well- microtitre plates with minor modifications. A stock so-

lution of 2 mg/ml of each of the test samples was prepared

in DMSO and subsequent dilutions were made with culture

medium. The test compounds in 20µl volume, concentration

at 50 µg/ml in a duplicate well were incubated with parasit-

ized cell preparation at 37º C in a candle jar. After 36-40 hr

of incubation the blood smears were prepared from each well

and stained with giemsa stain. The levels of parasitaemia in

terms of percentage of dead rings along with schizonts were

determined by counting a total of 200 asexual parasites mi-

croscopically using chloroquine as the reference drug.

RESULTS AND DISCUSSION

A series of 6-chloro-1,4-dihydro-2-phenyl quinoline-

4-carboxylic acid substituted with different aromatic alde-

hydes derivatives QC 1-6 were synthesized, characterized

and found in agreement with spectroscopic analysis as shown

in table no. 1. The FT-IR spectra of all the derivatives QC

1-6 nearer at 3300 cm-1 is due to the primary amino groups,

where as the medium peak in the region 1630-1580 cm-1

with N-H bending supports it. The strong absorption band

at 1335-1250 cm-1 confirms the existence of aromatic skel-

eton. The 1H-NMR spectrums reports a signal correspond-

ing to quinolyl protons at 6-8.5 ppm. The tested compounds,

QC-1, QC-5 and QC-6 have shown significant in-vitro anti

malarial efficacy under similar experimental conditions with

reference to the standard drug chloroquine.

The anti malarial screening result reflects that the com-

pounds QC-1, QC-5 and QC-6 possessing aromatic group

along with nucleophilic substitution with different alde-

hydes have shown comparatively a good in-vitro anti plas-

modic activity from 59 to 49 in comparison to chloroquine

under similar test conditions as mentioned in table no. 2.

Out of six evaluated compounds 6-chloro-2-(4-chlorophe-

nyl)-1, 4-dihydro-N’-phenyl quinoline-4-carbohydrazide

(QC-5) was found to be the most active against chloroquine

sensitive strain. These new hybrid series of novel quino-

line derivatives were found to be less effective than stan-

dard chloroquine. However their in-vitro results prove these

new quinolines have significant anti malarial activity which

needs further optimization for malarial chemotherapy.


COMPOUND

CODE

STRUCTURE

IUPAC NAME

Cl

O

C

N H

NH NH

OH

6-chloro-1,4-dihydro-

2-(2-hydroxyphenyl)-

N'-phenylquinoline-4-

QC-1 carbohydrazide


2-(3-hydroxy-4-

Cl methoxyphenyl)-N'-

phenylquinoline-4-

QC-2

OCH3

carbohydrazide

OH

O

C

NH NH


Cl 2-(3-methoxyphenyl)-

N'-phenylquinoline-4-

N

carbohydrazide

QC-3

OCH3

O

NH NH


QC-4

Cl

C 2-(3,4-dimethoxy

phenyl)-N'-phenyl

quinoline-4-

N H

carbohydrazide

OCH3

OCH3

6-chloro-2-(4-

O C

NH NH

chlorophenyl)-1,4-

Cl

dihydro-N'-phenyl

quinoline-4-

QC-5

N H

carbohydrazide

Cl

6-chloro-1,4-

C dihydroN',2-diphenyl

QC-6

Cl quinoline-4-

carbohydrazide

H

Table No. 1 List of synthesized novel quinoline derivatives


Table No. 2 In-vitro anti malarial activity of synthesized compounds QC 1-6

COMPOUNDS (50 µg/ml) Anti Malarial Activity (% dead rings+ schizonts) %

inhibition value / 200 parasites

QC-1 46

QC-2 40

QC-3 32

QC-4 36

QC-5 59

QC-6 58

Chloroquine (0.4 µg/ml) 71

CONCLUSION

A series of quinoline hybrids was synthesized and their

structures were validated by means of FT-IR, NMR and MS

analysis. The derivatives were evaluated for in-vitro anti

malarial activity against plasmodium falciparum (RPMI-

1640) strain with reference of chloroquine as a standard

drug of which three derivatives possess significant activity

among them 6-chloro-2-(4-chlorophenyl)-1,4-dihydro-N’-

phenyl quinoline-4-carbohydrazide (QC-5) shows highest

activity with electron withdrawing groups where as rest of

compounds with electron donating groups like 6-chloro-1,4-

dihydro-2-(2-hydroxyphenyl)-N’-phenylquinoline-4-carbo-

hydrazide shows mild to moderate activity.

However, it can be concluded that this class of com-

pounds with electron withdrawing groups possess potent

anti plasmodic activity than that of the compounds with

electron donating groups. Further research is needed in or-

der to determine the origin of this activity for development

of in vivo anti malarial activities.

REFERENCE

1. Lotta Glans, Dale Taylor, Carmen de Kock, Peter J.

Smith, Matti Haukka, John R. Moss, Ebbe Nordlander.

Synthesis, characterization and antimalarial activity of

new chromium arene- quinoline half sandwich com-

plexes Journal of Inorganic Biochemistry 2011; 105:

985-990.

2. B. Garudachari, M.N. Satyanarayana, B. Thippeswa-

my, C.K. Shivakumar, K.N. Shivananda, Gurumurthy

Hegde, Arun M. Isloor. Synthesis, characterization and

antimicrobial studies of some new quinoline incorpo-

rated benzimidazole derivatives European Journal of

Medicinal Chemistry 2012; 54: 900-906.

3. V.R. Solomon, H. Lee. Journal of Current Medicinal

Chemistry 2011; 18: 1488-1508.

4. S.M. Prajapati, K.D. Patel, R.H. Vekariya, S.N. Pan-

chal, H.D. Patel. RSC Advances 2014; 4: 1100-1104.

5. J.P. Michael. Natural Product Reports 2005; 22: 627-

646.

6. S. Levy, S.J. Azoulay. Journal of Cardiovascular Elec-

trophysiology 1994; 5: 635-636.

7. Hans Raj Bhat, Udaya Pratap Singh, Pankaj S. Yadav,

Vikas Kumar, Prashant Gahtori, Aparoop Das, Depak

Chetia, Anil Prakash, J. Mahanta. Synthesis, Charac-

terization and antimalarial activity of hybrid 4-amino

quinoline-1, 3, 5- triazine derivatives Arabian Journal

of Chemistry 2016; 9: S625- S631.


Zero Order Spectrophotometric Method Development and Validation for

Estimation of Cadexomer Iodine in Dosage Form

MAHESH.M*, S.SREE VIDYA, MANAMASA AJAY, KOLAR IRSHAD BASHA AND MANYAM VAMSIKRISHNA.

Department of Pharmaceutical Analysis, JNTUA - Oil Technological and Pharmaceutical Research Institute,

Ananthapuramu, A.P, India.

ABSTRACT

Purpose: Method developed and validated by using spectrophotometry for the estimation of Cadexomer

iodine in a dosage form.

Method: Cadexomer iodine in the solvent mixture [Distilled water and Methanol (3:1)] and its

absorbance was estimated by using UV-Visible spectrophotometry. Linearity, regression equation,

accuracy, precision, and standard deviation etc., parameters were calculated and were validated as

per ICH guidelines. Cadexomer iodine was determined in ointment dosage form using these validated

parameters.

Results: The λ (max) of Cadexomer iodine in the solvent mixture was found to be 225nm. The drug

follows the linearity in the concentration range 100-600 μg /ml with correlation coefficient value 0.9996.

The accuracy of the method was checked and recovery experiment performed at three different levels

i.e., 50%, 100%, and 150%. The % recovery was found to be in the range of 98-103%. The low values

of %RSD were indicated the method was precise, accuracy, reproducibility and Ruggedness.

Conclusion: The above-validated method may be useful for routine analysis of Cadexomer iodine in a

pharmaceutical dosage form.

Keywords: Cadexomer iodine, Distilled Water: Methanol (3:1), UV-Visible Spectrophotometry.

INTRODUCTION

It is chemically 2-hydroxy methylene cross-linked (1-4)-α-

D-glucan with Iodine1 and structure as shown in (fig-

1). It has broad-spectrum bacteriostatic activity against

organisms, including Staphylococcus aureus and

Pseudomonas aeruginosa. It is used for the treatment of

chronic exuding wounds such as leg ulcers, pressure ulcers

and diabetic ulcers infected traumatic and surgical wounds2.

It is an iodophor that is produced by the reaction of dextrin

with epichlorhydrin coupled with ion-exchange groups and

iodine. It is water soluble modified polymer containing 0.9%

iodine. One gram of cadexomer iodine ointment can absorb a

minimum of 2.5 ml of fluid. Iodine is physically immobilized

within the matrix of the dry cadexomer iodine and is slowly

released in an active form during uptake of wound fluid.

This mechanism of release provides antibacterial activity

both at the wound surface and within the formed gel. The

formed layer can easily be removed without damaging the

fragile new epithelium underneath absorbs exudates and

maintains a moist environment to promote healing o chronic

skin ulcers.

Structure of Cadexomer iodine (fig-1)

Correspondance E-mail: [email protected]

A Literature review was concluded by collecting different

articles related drug category and on the developed method

we move on to experiment3-12

Material and Methods

Instruments used:

A Shimadzu 1800 UV/VIS double beam spectrophotometer

with 1cm matched quartz cells was used for all spectral

measurements processed by UV-probe. Single Pan Electronic

balance (CONTECH, CA 223, India) was used for weighing

purpose. Sonication of the solutions was carried out using an

Ultrasonic Cleaning Bath (Spinco tech, India).

Materials used:

API of Cadexomer was procured as a gift sample by

Virchow Biotech Private Limited laboratories, Hyderabad,

India. Distilled water was prepared using Milli Q system

in laboratory and Methanol make SIGMA-ALDRICH.

Formulation of Cadexomer Iodine (Cadomer™10g) was

purchased from local pharmacy.

Method development

Selection of Diluent: Different Solvents like Water, 50%

Ethanol, Distilled water: Methanol (3:1) was employed

for recording of the UV spectrum and for the optimization

of the method. Solubility was found to be Distilled water:

Methanol (3:1).

Preparation of standard stock solution:

Standard Cadexomer iodine 100mg was weighed and

transferred to a 100ml volumetric flask and dissolved in



solvent mixture and the volume was made up to the mark

with solvent mixture in 100ml volumetric flask as it is a

1000µg/ml concentration. Optimized solution was prepared

from the stock solution with solvent mixture, which was

used as working standard.

Selection of Wavelength

100µg/ml was prepared from the standard stock solution

which is 1mg/ml and the samples were scanned in the wave

length range of 200-400 nm and the spectrum was observed

at 225nm. Solvent mixture was used as blank and reference.

Preparation of sample solution:

Sample solution was prepared by using 100mg of analyte

was weighed and dissolved in 100 ml diluent and the volume

was made up to the mark with diluent in 100ml volumetric

flask.

Calibration curve for Cadexomer Iodine

From the standard stock solution of Cadexomer iodine

appropriate aliquots were pipetted out in to 10 ml volumetric

flasks and dilutions were made with diluent to obtain

working standard solutions of concentrations from 100-600

μg/ml and the overlay spectrum shown fig-2.

Fig-2 Overlay Spectrum of Cadexomer Iodine

RESULTS AND DISCUSSION

In Zero order spectroscopy method the Cadexomer iodine

attains maxima absorption at 225nm; it showed good

linearity range in the concentrations of 100-600µg/ml. This

linearity range obeys beer-lambert’s law, and statistical data

of quantitative results obtained for this method shown in the

table-1. These results were subjected to statistical analysis to

find out standard deviation and standard error values and the

obtained results are below the precision of the methodology

hence the assay and accuracy was performed at three

different levels it confirms the method having repeatability

and reproducibility which has been validated as per ICH

guidelines [Q2 (R1)]

Table 1: Statistical data of Zero order Spectroscopic

method for Cadexomer Iodine:

Parameters Zero order spectroscopy

Cadexomer Iodine

max (nm) 225

Linearity range (µg/ml) 100-600 Regression equation (Y*) 0.0015x+0.001

Slope (m) 0.0015

Intercept (c) 0.001

Correlation coefficient (r2) 0.9996

Precision Interday

(%RSD) 0.438

Precision Intraday

(%RSD) 0.859

LOD (µg/ml) 6.01

LOQ (µg/ml) 18.22

METHOD VALIDATION

LINEARITY:

The proposed linearity range of the study was carried out by

plotting concentration against absorbance of the analyte it

shows a good relationship between concentrations and the

absorbance of the Cadexomer Iodine. The linearity graph is

shown in fig 3.

Fig 3. Linearity graph for Cadexomer iodine

ACCURACY:

The accuracy was performed for this method by conducting

recovery studies of triplet standard addition method at

different concentration levels of 50%, 100% and 150%. By

adding known amount of Cadexomer iodine to pre analysed

samples and was subjected to the proposed method. Results

of recovery studies are shown in table 2.


Table 2: Accuracy data

Cadexomer Iodine

Recovery

Range

Spiked

conc.

Amount added

(µg/ml)

Amount found

(µg/ml) % recovery % Mean recovery

50%

200

50.01

49.837 101.09

100.21

50.814

50.977

100%

400

100.00

99.672

100.99 100.164

100.657

150%

600

150.03

148.526 99.45

151.965

147.052

PRECISION:

The method shows repeatability and reproducibility by

the estimated sample analysis which has been done by six

replicates of fixed concentration from the formulation. The

Interday and intraday also conducted at confidence interval

and the results obtained. The %RSD was found below the

2% it indicates that as good precision for the method these

results were tabulated in table3.

Table 3: Precision Data

Sl.No. Inter Day Intra Day

1 0.622 0.610

2 0.624 0.614

3 0.625 0.616

4 0.620 0.622

5 0.628 0.622

6 0.623 0.623

Mean 0.623666667 0.617833333

Std.Dev 0.00273 0.00530

%RSD 0.44 0.86

DETECTION OF LIMITS (LOD & LOQ):

The detection limit of an individual analytical procedure

is the lowest amount of analyte in a sample which can be

detected but not necessarily quantitated as an exact value.

The limit of detection of analyte can be calculated LOD=3.3

* standard deviation (σ)/ s. The Limit of quantitation

LOQ=10* standard deviation (σ)/ s. The results of LOD &

LOQ were tabulated in table 1.

ROBUSTNESS:

It demonstrates the analytical method which will unaffected

while small changes made in the analytical procedure, but

deliberate variations in method parameters and provides

an indication of its reliability during normal usage. The

robustness data were shows in table 4.

Table 4: Robustness data

S.No. Robust

Condition Parameter %RSD

1 Wave length

± 3 nm

222nm 0.63 2 225nm 0.49 3 228nm 0.47

CONCLUSION:

The zero order spectroscopy method for the estimation of

Cadexomer iodine has been successfully developed and

validated and the method adheres to regulatory requirements

for linearity, accuracy, precision and recovery studies. This

method can be applied for the routine quality control analysis

of analyte in dosage form.

ACKNOWLEDGEMENT

I am very thankful to Director, JNTUA-OTPRI,

Ananthapuramu for providing the laboratory facilities,

chemicals to carryout entire research work.

REFERENCES

1. https://newdrugapprovals.org/2018/04/18/cadexomer-iodine.

2. Dr Low Lian Leng , 2015. wound care, the Singapore family

physician, 41(2);27.

3. Schultz GS, Sibbald RG, Falanga V, 2003. Wound bed preparation:

a systematic approach to wound management. Wound Repair

Regen; 11:1-28.

4. https://en.wikipedia.org/wiki/Cadexomer_iodine.

5. Shivani, Ajay Kumar Kpilesh, Megha Sharma 2014. Validation

and Analytical Method Development for Determination of

Ornidazole in Ointment Formulation by U.V Spectrophotometric

Method. International Journal of Pharmaceutical Technology and

Biotechnology; 1(1):01-10.

6. Yasuhiro Noda, Kiori Fujii , Satoshi Fujii 2009. Critical evaluation

of cadexomer-iodine ointment and povidone-iodine sugar ointment.

International Journal of Pharmaceutics; 372: 85–90.

7. Arti P Parmar, DilipG. Maheshwari. 2015. Simultaneous Estimation

of Mupirocin and Mometasone Furoate In Pharmaceutical Dosage


Form By Q-Absorption Ratio Method. International Journal of

Pharma Sciences and Research; 5 (2): 1-7.

8. B. Karthik kumar, V.S. Thiruvengada rajan, N. Tanveer begum

2012. Analytical Method Development and Validation of Lidocaine

in Ointment Formulation by U.V Spectrophotometric Method.

International Journal of Pharmacy and Pharmaceutical Sciences;

4(2): 610-614.

9. G. A. Shabir and T. K. Bradshaw 2010. Determination of 1, 7, 7-

trimethyl-bicyclo(2,2,1)heptan-2-one in a cream pharmaceutical

formulation by reversed-phase liquid chromatography. Indian Journal

of Pharmaceutical Sciences; 72 (6): 809-814.

10. Rushikesh J. Lohar, Vipul M. Patil, Ravindra G. Gaikwad,

Shitalkumar S. Patil, 2016. Development And Validation Of UV-

Visible Spectrophotometric Method For Estimation Of Selected

Antiseptic Drug In Bulk And Pharmaceutical Dosage Form. World

Journal Of Pharmacy And Pharmaceutical Sciences, 5( 9):1197-1205

11. Deepak V. Bageshwar, Avinash S. Pawar, Vineeta V. Khanvilkar,

Vilasrao J. Kadam, 2010. Quantitative Estimation Of Mupirocin

Calcium From Pharmaceutical Ointment Formulation By UV

Spectrophotometry. International Journal of Pharmacy and

Pharmaceutical Sciences. 2(3): 86-88.

12. Gunasekar Manoharan, 2016. Development And Validation Of

A Stability-Indicating Rp-Hplc Method For The Estimation Of

Mupirocin In Bulk And Ointment Dosage Form . European Journal

Of Pharmaceutical And Medical Research. 3(10): 470-476.


Analytical Method Development and Validation of Venlafaxine Hydrochloride

Assay by RP-HPLC in Bulk and Pharmaceutical Dosage Form

K.S.NATARAJ*, A. SRINIVASA RAO AND R.SURYA SANTHOSH

1Shri vishnu college of pharmacy, Bhimavaram, West Godavari ,

Andhra pradesh, India, Pincode-534202.

ABSTRACT

OBJECTIVES: The present article involved the development of sensitive and validated reverse phase

liquid chromatographic method for the determination of Venlafaxine Hydrochloride by RP-HPLC

in bulk and pharmaceutical dosage form . Method: Isocratic elution at a flow rate of 1.0 ml / min was

employed on a Kromasil, 100-A, C8 (250x4.6) mm, 5µm at 30ºC. The mobile phase consisted of mixture

of Methanol: Water in the ratio of 90:10(%V/V) respectively and the UV detection wavelength was 225

nm. Results: The drug in the concentration range of 5-25 μg/ml with regression coefficient 0.9968

at 225 nm. The RT value of Venlafaxine Hydrochloride was found to be 4.7 min, respectively with a run

time of 10 min. The proposed method was successfully applied to the determination of Venlafaxine

Hydrochloride bulk and pharmaceutical dosage form. The method was found linear over the range of

0 – 25 μg/ml. The recovery was observed in the range of 98% to 102% and limit of detection and limit of

quantification were found to be 0.299 μg/ml and 0.908 μg/ml. Different analytical parameters such as

precision, accuracy, limit of detection, limit of quantification and robustness were determined and found

satisfactory according to International Conference on Harmonization (ICH) guidelines. Conclusion:

The developed methods were found reliable, easy and validated for the estimation of Venlafaxine

Hydrochloride in bulk and pharmaceutical dosage form.

KEYWORDS: Venlafaxine Hydrochloride, RP-HPLC, Isocratic elution, ICH Guidelines, Validation.

INTRODUCTION:

Venlafaxine Hydrochloride (Fig: 1) is chemically 1-[2-

(dimethylamino)-1-(4-methoxyphenyl) ethyl]

cyclohexan-1-ol.Venlafaxine is used to treat depression1,2.

It may improve your mood and energy level, and may help

restore your interest in daily living. Venlafaxine is known

as a serotonin-norepinephrine reuptake inhibitor (SNRI). It

works by helping to restore the balance of certain natural

substances (serotonin and norepinephrine) in the brain1,2,3.

The reported methods of Venlafaxine Hydrochloride assay

with RP-HPLC are very few when literature survey was

done found a simultaneous estimation method , bulk drug

estimation and pharmaceutical dosage form estimation is

found separately so there is really a need to develop a

method for venlafaxine hydrochloride assay by RP-HPLC in

bulk and pharmaceutical dosage3,5,6 form which is reliable,

easy, fast and validated method for the estimation of

venlafaxine hydrochloride. Therefore, efforts has been

taken by the authors to develop a reliable, fully validated and

stability indicating method for the estimation of Venlafaxine

Hydrochloride in bulk and marketed dosage form in

accordance with the International Conference on

Harmonization (ICH) Guidelines Q2B for the validation

of analytical procedure.

Correspondance - Email: [email protected]

Figure 1: Structure of Venlafaxine Hydrochloride

MATERIALS AND METHODS:

Instrumentation:

High performance liquid chromatography (Shimadzu) is

equipped with UV detector by using column Kromasil, 100-

A, C8 (250x4.6) mm, 5µm.Data processing was carried out

by open lab software, Electronic balance (Eutech), pH meter

(Systronics), ultra sonicator (Life care equipment’s)

Reagents and Chemicals Used:

The active pharmaceutical ingredient Venlafaxine

HCL (99.46% purity) was kindly obtained from the

AUROBINDO PHARMA LIMITED, Hyderabad, India.

Venflaxine HCL tablets Purchased from local pharmacy.

Methanol, acetonitrile, used were HPLC grade form Loba



chemicals, Mumbai, India. HPLC grade distilled water

is used from Millipore. Dipotassium hydrogen phosphate,

orthophosphoric acid, hydrochloric acid were analytical

grade and from Research lab chem Industries, Mumbai.

The solvents were filtered through 0.45µ membrane filter

and sonicate before use.

Chromatographic Conditions:

The chromatographic mode used in this method was RP-

HPLC and the detector used in this was UV detector.

Kromasil C8-100 (250 × 4.6 mm, 5 µm) was used as

stationary phase and the mobile phase used in this method

was Methanol: Water (90:10). The wave length used for

detection was 225.0 nm. Flow rate was maintained at 1.0 ml/

min and the injection volume was 20.0 µL. The Venlafaxine

HCL peak was well resolved with good peak shape and

symmetry and less retention time made this condition more

acceptable, also in the economic point of view.

EXPERIMENTAL WORK:

Preparation of standard:

Weighed accurately 100 mg of Venflaxine HCL, transferred

into 100 ml Standard flask, dissolved and made up to the

volume-using methanol and water (90:10). This solution

had a Concentration of 1 mg per ml of Venflaxine HCL.

Accurately pipetted out 10ml of aliquot separately into 100

ml standard flask and the volume was made up to 100 ml

using methanol and water (90:10). The resulting solution

had a concentration of 100μg/ml of Venflaxine HCL.

Accurately pipetted out 1ml of solution B separately

into 10 ml standard flask and the volume was made up

to 10 ml using methanol and water (90:10). The resulting

solution had a concentration of 10μg/ml of Venflaxine HCL.

Preparation of Sample Solution:

Twenty pharmaceutical dosage forms were taken and

determined the average weight. Above weighed tablets

were finally powdered and triturated well. A quantity of

powder equivalent to 200 mg of drugs were transferred to

200 ml clean and dry volumetric flask, added about 100 mL

of Acetonitrile sonicated for 10 minutes with intermittent

shaking at room temperature. Then added 100mL of Water,

sonicated for 20minutes. Diluted 2mL of the Supernatant

solution to 50mL with mobile phase.

Selection of wavelength : The standard and sample stock

solutions were prepared separately by dissolving standard

and sample in a solvent in mobile phase diluting with

the same solvent. (After optimization of all conditions)

for UV analysis. It scanned in the UV spectrum in the range

of 200 to 400nm. This has been performed to know the

maxima of Venlafaxine HCL, so that the same wave

number can be utilized in HPLC UV detector for estimating

the Venlafaxine HCL. While scanning the Venlafaxine

HCL solution we observed the maxima at 225 nm.

METHOD VALIDATION:

1. System suitability: The main purpose of the system

suitability is to ensure the system including instrument,

analyst, chemicals and electronics are suitable to the intended

application. One standard injection and five replicate system

suitability solution injections were injected. The % RSD for

the retention times and peak area of Venlafaxine HCL was

found to be less than 2%.

2. Specificity:

Blank interference:

Blank was prepared and injected as per test method. It

was observed that no blank peaks were interfering with

analytical peaks.

Placebo interference:

Placebo solutions were prepared in duplicate and

injected as per test method. It was observed that no placebo

peaks were interfering with analytical peaks.

Tablet sample preparation:

10 mg of Venlafaxine HCL tablets was taken into a mortar

and crushed to fine powder and uniformly mixed. Tablet

stock solutions of Venlafaxine HCL (microgram/ml) were

prepared by dissolving equivalent weight 113.5 mg in 10

ml of Acetonitrile. Sonicate for 5 min. After that, filter the

solution using 0.45-micron syringe filter. Further dilution

of 15μg/ml of Venlafaxine HCL was made by adding 0.15

ml of stock solution to 10 ml of Methanol: water (90:10).

3. Linearity and range:

The linearity of an analytical procedure is its ability to

obtain test results which are directly proportional to

the concentration of analyte in the sample. Solutions

were prepared in the range of 5-50 μg/ml and injected.

Regression coefficient was calculated by plotting a graph

between concentration of the solutions on the X-axis and

responses of the corresponding solutions on the Y-axis. Fig:

4, Table: 41

4. Accuracy/Recovery: Accuracy of the method was

determined by recovery studies. To the formulation (pre

analyzed sample), the reference standards of the drugs

were added at the level of 50%, 100%, 150%. The recovery

studies were carried out three times and the percentage


recovery and percentage mean recovery were calculated

for drug is shown in table. To check the accuracy of the

method, recovery studies were carried out by addition of

standard drug solution to pre-analyzed sample solution at

three different levels 50%, 100%, 150%. The % recovery of

Venlafaxine should lie between 98% and 102%. The RSD of

all the recovery values should not be more than 2.0% .

5. Method precision: Prepared sample preparations of

Venlafaxine hydrochloride as per test method and injected

6 times in to the column. The relative standard deviation of

6 determinations of Venlafaxine HCL for intra and inter day

precision found to be within the acceptance criteria of less

than 2.0% .

6. Limit of Detection: The detection limit of an individual

analytical procedure is the lowest amount of the analyte in a

sample which can be detected but not necessarily quantitated

as an exact value. The % RSD values for LOD was found to

be less than 2 and hence the result found to be satisfactory.

7) Limit of Quantification: The detection limit of an

individual analytical procedure is the lowest amount of the

analyte in a sample which can be quantitatively determined

with suitable precision and accuracy. The % RSD value for

LOQ was found to be less than 2 and hence the result found

to be satisfactory .

8) Robustness: Small deliberate changes in method like

flow rate, mobile phase ratio, and temperature are made

but there were no recognized change in the result and are

within range as per ICH Guide lines. The Tailing Factor of

Venlafaxine HCL standard should not be more than 2.0.The

Tailing Factor of Venlafaxine HCL standard should not

be more than 2.0 for Variation in Flow.The Tailing Factor

Venlafaxine HCL standard and sample solutions should not

be more than 2.0.Table: 3

RESULTS AND DISCUSSIONS:

The optimised chromatographic conditions were utilized

for method validation study and force degradation study

as per ICH guidelines for the method development and

validation. System Suitability was tested for verifying the

adequate working of the equipment used for analytical

measurements. Parameters such as tailing and theoretical

plates were taken into consideration. The % RSD for

the retention times and peak area of Venflaxine HCL was

found to be less than 2%. The plate count and tailing factor

results were found to be satisfactory and are found to be

within the limit. In the study of specificity no correspond

peak was found at the retention time of the analyte. The

percentage purity of Venflaxine HCL marketed dosage

form using developed HPLC method was conducted and

found to be 99.3% , which is within limits. The calibration

curve showed linearity in the range of 5 – 40 μg/ml, for

Venlafaxine HCL(API) with correlation coefficient (r2) of

0.996. The Minimum concentration level at which the

analyte can be detected (LOD) and quantified (LOQ) were

found to be 0.299and 0.908μg/mL respectively. In the study

of intra and interday precision, the % RSD was found 0.529

and 0.597. The accuracy of the developed method was

proved by conducted the recovery study. The average

recovery of the Venflaxine HCL using HPLC method was

99.3%. The method was robust with the change in flow rates

from ±0.2 mL/min, acetonitrile and methanol ratios (87:13,

90:10, 93:7), Detection wavelength (223, 227 and 229). he

details of the study results are presented in Table-3

Table 1: Summary of validation parameters:

Parameters Venflaxine HCL at 225nm

Regression equation Y=3746.9x+17537

Slope 3746.9

Intercept 17537

Co-relation co-efficient 0.9968

LOD mg/ml 0.299

LOQ mg/ml 0.908

Precision (% RSD) 0.529

CONCLUSION:

After seeing all the satisfactory results in optimized

chromatographic conditions and validation parameters. It

may conclude that this newly developed method is simple,

specific and easy to perform and requires shorter time to

analyze the sample. Low limit of quantization and limit

of detection makes this method suitable for use in quality

control. This method enables determination of Venlafaxine

HCL because of good peak shape and high value of

theoretical plates with the use of water as a part of mobile

phase. This method was found to be accurate, precise, linear,

and robust as per ICH Q2B guidelines for analytical method

development. Hence this method can be successfully use for

the routine analysis of Venlafaxine HCL in Bulk and Tablet

dosage form.

ACKNOWLEDGEMENT : The authors are thankful

to the Shri Vishnu college of pharmacy, Bhimavaram, for

providing the necessary facilities to carry out the research

work.


Table 2: Assay of marketed formulation by RP-HPLC method.

Tablet Formulation Formulation Labelled

amount of Drug (mg)

amount (mg) found by

the proposed method % Recovery

Venflaxine HCL 100 99.3 99.3

Table 3: Robustness study

Robustness Parameter Rt T

f

Flow rate (mL min-1)

0.8

1.0(optimized)

1.2

MobilePhase composition(%v/v)

87:13

90:10

93:7

Wavelength variation(nm)

223

227

229

8.846

7.094

5.961

10.15

6.98

6.13

6.98

6.98

6.95

1.62

1.58

1.61

1.27

1.54

1.56

1.53

1.54

1.52

Figure 2: Optimized Chromatogram


Figure 3: Assay of tablet dosage form by developed HPLC method

Figure 4: Graph for Linearity data of Venlafaxine HCL

ABBREVIATIONS : RP HPLC: Reverse phase High

performance liquid chromatography; LOD: Limit of

detection; LOQ: Limit of quantitation; RSD: Relative

standard deviation; U V: Ultra violet; ICH: International

conference on Harmonization.

REFERENCE:

1. Drug Facts, Side Effects and Dosing. www.medicinenet.com/

venlafaxine/article.htmVimal D.

2. Shirvi, Vijaya Kumar G. and Channabasavaraj K.P. Second

order derivative spectrophotometric estimation of Venlafaxine

hydrochloride in bulk and pharmaceutical formulations. IJCRGG

Vol.2, No.1, pp 572.

3. Pillai S and Singhvi I. Spectrophotometric methods for estimation of

Venlafaxine from tablet formulation. Indian Pharmacist 2006; 5(48)-

75.

4. Deepam M, Prakash M, Rajasekhar S, Jayaseelan. Development and

validation of HPLC method for assay of Venlafaxine Hydrochloride,

API. 2008.

5. Matoga M, Pehoureq F. Rapid HPLC measurement ofVenlafaxine

and O- desmethyl Venlafaxine in Human plasma: J.chromatogra B

Biomed Sci Appl. (760), 2001,213-218.

6. 37.Vimal D. Shirvi, Vijaya Kumar G. and Channabasavaraj

K.P. Second order derivative spectrophotometric estimation of

venlafaxine hydrochloride in bulk and pharmaceutical formulations.

IJCRGG Vol.2, No.1, pp 572-75.

http://www.medicinenet.com/


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October-December 2019 19 Journal of Pharmacy and Chemistry . Vol. 13 . Issue.4

.

.

ENHANCEMENT OF SOLUBILITY BY SOLID DISPERSION TECHNIQUE – A REVIEW

Lubna Nousheen1,3*, S. Rajasekaran2, Mohd. Shoukhatulla Ansari3

1Research Scholar, Department of Pharmaceutics, Bhagwant University Ajmer, Rajasthan, India. 2Malik Deenar College of Pharmacy, Seethangoli, Bela, Kasaragod - 671321, Kerala, India

3Anwarul Uloom College of Pharmacy, New Mallepally, Hyderabad – 500001, Telangana, India.

ABSTRACT

Improving oral bioavailability of drugs those given as solid dosage forms remains a challenge

for the formulation scientists due to solubility problems. Most of the newly developed chemical

entities are poorly water soluble. As a result, formulating them as oral solid dosage forms is a

hurdle to the specialists. Many techniques have been exercised to improve oral bioavailability

of drugs. Among several methods, solid dispersion has attracted attention of the researchers for

previous 50 years. Different formulation strategies have been taken to prepare solid dispersions.

It is evident that solid dispersions enhance solubility of medicinal particles and thereby

improving the degradation properties of drugs that maximize oral bioavailability. This work will

focus on various aspects of solid dispersion preparation, their benefits, and major challenges.

Keywords: Solid dispersion, Amorphous, Poorly soluble drugs, Dissolution rate, Solubility.

INTRODUCTION

When a medication is administered orally in solid dosage

forms such as tablets, capsules or suspension it must be

discharged from dosage form and liquefy in

gastrointestinal liquid before it can be absorbed. The low

aqueous solubility and dissolution rate of API is one of

the major challenges in pharmaceutical production and

has become more popular among newcandidates over the

past two decades due to the use of high-performance and

combinatorial screening tools during the drug discovery

and selection process, which are in effect regulated by

the surface area [1-3]. Different approaches to deal with

the poor aqueous solubility of drug candidates have been

explored in drug research and development for

example,particle size reduction [4], prodrug formation

[5], solid– lipid nanoparticle [6], salt formation [7],

micro-emulsions [8], nano-emulsions [9], complexation

[10], nanosuspensions [11],micelles [12], and solid

dispersion, considered to be one of the most successful

strategies for improving poorly soluble dissolution

profile. In the Biopharmaceutical Classification System

(BCS) drugs with low aqueous solubility and high

membrane permeability are categorized as Class II drugs.

________________________________

Therefore, solid dispersion technologies are specially

promising to improve the oral absorption and

bioavailability of BCS Class II drugs [13].

SOLID DISPERSION

Solid dispersion (SD) method has been widely utilized to

increase the rate of dissolution, solubility and oral

retention of ineffectively water-soluble medicines [14,

15]. The word solid dispersion refers to the dispersal of

at least one or more major ingredients in an inert carrier

or matrix at solid state organised by melting (fusion),

solvent or the melting – solvent methods [16].The API in

solid dispersions can be dispersed in separate molecules,

amorphous particles, or crystalline particles while the

carrier can be in crystalline or amorphous state.

Numerous studies on solid dispersions have been

reported and have shown severalbenefits of solid

dispersions in enhancing the solubility and dissolution

rate of poorly water-solubleproducts. Such benefits

include reducing particle size, possibly to molecular

level, enhancing wettability and porosity, as well as

changing drug crystalline state, preferably into

amorphous state [17].

*Corresponding author: [email protected]


Table -1

BCS system of classification

Class Solubility Permeability Drugs

Class I High solubility High permeability Sumatriptan, Benzapril, Loxoprofen, etc.

Class II Low solubility High permeability Nimesulide, Loratadine, Glimepiride etc.

Class III High solubility Low permeability Atropine, Gabapentine, Topiramate, etc.

Class IV Low solubility Low permeability Furosemide, Hydrochlorthiazide, Meloxicam etc.

Table -2

Different Materials used for solid dispersion as carrier S.No. Carriers Materials Examples

1 Acids Citric acid, succinic acid

2

Polymeric materials

hydroxy ethyl cellulose, polyethylene glycol (PEG), hydroxypropyl methyl

cellulose, methyl cellulose, Povidone (PVP), cyclodextrin, hydroxy propyl

cellulose, pectin, galactomannan

3 Sugars Galactose, sorbitol, dextrose, sucrose, maltose, xylitol mannitol, lactose

4 Surfactants Polyoxyethylene stearate, renex, poloxamer 188, texafor AIP, deoxycholic

acid, tweens, spans

5 Enteric polymer (insoluble) HPMC phthalate, eudragit S100, eudragit L100, Eudragit RL, Eudragit RS

6 Others Pentaerythrityl tetraacetate, urea, Pentaerythritol, urethane, hydroxy alkyl

xanthins

Despite such high active research interests, the number

of products marketed as a result of solid dispersion

approaches is deceptively low. This low number is

mainly due to scale-up problems and physicochemical

instability in the manufacturing process or during storage

leading to phase separation and crystallization [18-21].

Only a few commercial products have been marketed

during the past half-century (Table 3).Therefore, in-

depth knowledge gained on various aspects of solid

dispersions such as carrier properties, preparation

methods, physicochemical characterization techniques as

well as the pharmaceutical mechanism of matrix

formation and drug release are very important to ensure

the preparation of a productive and marketable solid

dispersion.

Table -3:

Different marketed products using Solid Dispersions[22-24].

S. No. Product Model drug Carrier type Dosage form

1 Intelence Etravirine HPMC Tablet

2 Kaletra Lopinavir, Ritonavir PVPVA Tablet

3 Certican Everolimus HPMC Tablet

4 Nivadil Nivaldipine HPMC Tablet

5 Gris-PEG Griseofulvin PEG Tablet

6 Cesamet Nabilone PVP Tablet

7 Zelboraf Vemurafenib HPMCAS Tablet

8 Incivek Telaprevir HPMCAS-M Tablet


Types of Solid Dispersions

A. Based on carrier used [25]

B. Based on molecular arrangement [26]

A. Based on carrier used:On the basis of carrier

used solid dispersions can be classified into

three generations:

1. First generation: Using crystalline carriers

such as urea and sugars, first generation solid

dispersions were prepared which were the first

carriers to be employed in solid dispersions.

They have the demerits of forming crystalline

solid dispersions and did not release the drug as

quickly as amorphous ones.

2. Second generation: Second generation solid

dispersions include amorphous carriers instead

of crystalline carriers which are usually

polymers. These polymers include synthetic

polymers such as povidone (PVP),

polyethyleneglycols (PEG) and

polymethacrylates as well as natural products-

based polymers such as hydroxylpropylmethyl-

cellulose (HPMC), ethyl cellulose, and

hydroxypropylcellulose or starch derivatives

like cyclodextrins.

3. Third generation: Recently, it has been shown

that the dissolution profile can be improved if

the carrier has surface activity or self-

emulsifying properties. Therefore, third

generation solid dispersions appeared. The use

of surfactant such as inulin, inutec SP1,

compritol 888 ATO, gelucire 44/14 and

poloxamer 407 as carriers was shown to be

effective in originating high polymorphic purity

and enhanced in vivo bioavailability.

B. Based on molecular arrangement:Solid

dispersions can be classified in following types:

1. Eutectics Systems: This mixture consists of

two compounds which in the liquid state are

completely miscible but in the solid state only

to a very limited extent. By rapid solidification

of the fused melt of two components these are

prepared and that show complete liquid

miscibility and minor solid-solid solubility as

shown in Fig.1.

Fig. 1:Phase diagram of a Eutectic System

Thermodynamically, such a system is an intimately

blended physical mixture of two crystalline components.

When the mixture of A and B with a fix composition is

cooled, A and B crystallize out simultaneously, whereas

when other compositions are cooled, one of the

components starts to crystallize out before the other.

When a mixture containing slightly soluble drug and

carrier as an inert substance and highly water soluble is

dissolved in an aqueous medium, the carrier will dissolve

fast, releasing very fine crystals of the drug [27].

2. Amorphous precipitation in a crystalline carrier: In

the crystalline carrier the drug may also precipitate in

an amorphous form instead of simultaneous

crystallization of the drug and the carrier (eutectic

system). The amorphous solid state is shown in Fig. 2.

The high energy state of the drug in this system

generally produces much greater dissolution rates than

the corresponding crystalline forms of the drug [28].

Fig. 2: Amorphous solid solution

3. Glass solutions and suspensions: These are the

homogeneous glassy system in which solute is

October-December 2019 Journal of Pharmacy and Chemistry . Vol. 13 . Issue.4

dissolved in glass carrier. Glass suspensions are

mixtures in which precipitated particles are

suspended in glass solvent. Lattice energy is

much lower in glass solutions and suspensions.

Melting points of glasses is not sharp while they

soften progressively on heating. Examples of

carriers that form glass solutions and

suspensions are citric acid, PVP, urea, PEG,

sugars such as dextrose, sucrose, and galactose

[29].

4. Solid Solutions: In this system a homogeneous

one phase system is formed when the two

components crystallize together. The particle

size of the drug is reduced to its molecular size

in the solid solution. Thus, a faster dissolution

rate is achieved in a solid solution than the

corresponding eutectic mixture. Solid solutions

can be classified as continuous or discontinuous

according to the extent of miscibility of the two

components. In continuous solid solutions, the

two components are miscible in the solid state

in all proportions [30].

a) Continuous Solid Solutions: The components

are miscible in all proportions in a continuous

solid solution. Hypothetically, this means that

stronger the bonding strength between the two

components than the bonding strength between

the molecules of each of the individual

components [31].

b) Discontinuous Solid Dispersions:

The solubility of each of the components in the

other component is limited in the case of

discontinuous solid solutions. A typical phase

diagram (Fig.3) shows the regions of true solid

solutions. One of the solid components is

completely dissolved in the other solid

component in these regions. The mutual

solubility’s of the two components start to

decrease below a certain temperature. Goldberg

reported that the term `solid solution' should

only be applied when the mutual solubility of

the two components exceeds 5% [32].

Fig.3: Phase Diagram for Discontinuous solution

c) Substitutional crystalline solid solutions: A

substitutional crystalline solid dispersion is depicted

in Fig. 4 in which the solute molecules substitute for

the solvent molecules in the crystal lattice.

Substitution is only possible when the size of the

solute molecules differs by less than 15% or so from

that of the solvent molecules[33].

Fig. 4: Substitutional crystalline solid solution

d) Interstitial Crystalline Solid Solution:In

interstitial solid solutions, the dissolved

molecules occupy the interstitial spaces between

the solvent in the crystal lattice as shown in

Fig.5. The solute molecules should have a

molecular diameter that is no greater than 0.59

times than that of the solvent molecular

diameter and the volume of the solute molecules

should be less than 20% of the solvent [34].

Fig. 5: Interstitial Crystalline solid solution

22


Mechanism of drug release from solid

dispersions

There are two main mechanisms of drug release from

immediate release solid dispersions: drug-controlled

release and carrier-controlled release. When solid

dispersions are dispersed in water, the carriers often

dissolve or absorb water rapidly due to their hydrophilic

property and form concentrated carrier layer or gel layer

in some cases. If the drug dissolves in this layer and the

viscosity of this layer is high enough to prevent the

diffusion of the drug through it, the rate limiting step will

be the diffusion of the carrier into the bulk phase and this

mechanism is carrier-controlled release. If the drug is

insoluble or sparingly soluble in the concentrated layer, it

can be released intact to contact with water and the

dissolution profile will depend on the properties of drug

particles (polymorphic state, particle size, drug

solubility) [35].

In fact, these two mechanisms often occur

simultaneously because the drug may be partly soluble or

entrapped in the concentrated carrier layer. However,

these mechanisms help explain the different release

behaviors of solid dispersions and figure out the way to

improve the dissolution profile of solid dispersions.

Numerous researches showed the improvement of drug

dissolution profile when the ratio of carriers in solid

dispersions was increasedbecause the drug was dispersed

better and the drug crystallinity decreased [36].In these

solid dispersions the main release mechanism is drug-

controlled release. In contrast, other researches

demonstrated the decrease in drug dissolution rate when

the ratio of carrier in solid dispersions was increased

[37].This can be explained by the carrier-controlled

mechanism in which the gel orconcentrated carrier layer

is formed and acts as a diffusion barrierto delay drug

release. The release mechanism may also be affected by

the ratio of drug–carrier in solid dispersions. Karavas et

al. [38]prepared felodipine solid dispersions by using

different types of PVP, PEG as carriers and concluded

that the proportion of the drug in solid dispersions

determined the mechanism of drug release which was

drug diffusion (through the polymer layer)-controlled at

low drug contents and drug dissolution-controlled at high

drug contents. Therefore, in order to improve the

dissolution profile of solid dispersions, it is important to

identify the mechanism release of solid dispersions rather

than only focus on the polymorphic state of drugs

because in carrier-controlled release solid dispersions,

the carrier properties such as solubility, viscosity, gel

forming ability and the ratio of drug–carrier are the key

factorsaffecting the drug dissolution profile [39].

Techniques for Solid Dispersions: [40]

Various methods of preparation solid dispersions are

summarized as:

1. Solvent Evaporation

2. Hot-Melt Extrusion

3. Fusion Method

4. Solvent Melt Method

5. Kneading Technique

6. Direct Capsule Filling

7. Melt Agglomeration Method

8. Dropping Method

9. Supercritical Fluid Method

10. Lyophillization Techniques

11. Spray-Drying Method

12. Gel Entrapment Technique

13. Co-Precipitation Method

14. Co-Grinding Method

15. Electro Spinning Method.

16. Use of Surfactant

1. Solvent evaporation

In this method, the physical mixture of the drug and

carrier is dissolved in a common solvent, which is

evaporated until a clear, solvent free film is left. The film

is further dried to constant weight. The main advantage

of the solvent method is thermal decomposition of drugs

or carriers can be prevented because of the relatively low

temperatures required for the evaporation of organic

solvents [41].

2. Hot-melt extrusion

In recent years, hot melt extrusion has become one of the

most common methods for solid dispersion preparation

due to its high scalability and applicability. In this

method, the drug and carrier are simultaneously mixed,

23


heated, melted, homogenized and extruded in a form of

tablets, rods, pellets, or milled and blended with other

excipients for different purposes [42]. The intense

mixing and agitation forced by the rotating screw during

the process cause disaggregation of drug particles in the

molten polymer, resulting in a homogenous dispersion

[43].This process involves the transformation of a solid

mass of intertwined particles into a viscous liquid or

semisolid mass by heating and intense mixing. The hot

melt extruded systems are composed of drugs, one or

more meltable polymers and other additives such as

plasticizers and pH modifiers. The melting rate is mainly

affected by the physical and rheological properties of the

polymer. The melting rate is much faster when polymers

are amorphous and low viscous. Hot melt extrusion of

miscible components may lead to a high trend of

amorphous solid dispersion formation, thus improving

drug dissolution profile. In order to select a suitable

polymer for hot melt extrusion process, Hansen

solubility parameter can be applied to predict the drug–

carrier miscibility [44-45].Despite some problems such

as the miscibility of drugs and carriers as well as high

local temperatures in the extruder due to high shear

forces, ho melt extrusion has considerable advantages for

pharmaceutical applications. An important advantage of

the hot melt extrusion method compared to other melting

methods is the low residence time of the drug and carrier

at elevated temperature in the extruder which reduces the

risk of degradation of thermolabile drugs [46]. This

method is also continuous, efficient, easy scale-up and

produce higher thermodynamic stability products than

other methods [47].

3. Fusion method

The melting or fusion method, first proposed by

Sekiguchi and Obi involves the preparation of physical

mixture of a drug and a water-soluble carrier and heating

it directly until it melted. The melted mixture is then

solidified rapidly in an ice-bath under vigorous stirring.

The final solid mass is crushed, pulverized and sieved.

Appropriately this has undergone many modifications in

pouring the homogenous melt in the form of a thin layer

onto a ferrite plate or a stainless steel plate and cooled by

flowing air or water on the opposite side of the plate. In

addition, a super-saturation of a solute or drug in a

system can often be obtained by quenching the melt

rapidly from a high temperature [48].Under such

conditions, the solute molecule is arrested in the solvent

matrix by the instantaneous solidification process. The

quenching technique gives a much finer dispersion of

crystallites when used for simple eutectic mixtures.

4. Solvent melt method

It involves preparation of solid dispersions by dissolving

the drug in a suitable liquid solvent and then

incorporating the solution directly into the melt of

polyethylene glycol, which is then evaporated until a

clear, solvent free film is left. The film is further dried to

constant weight. The 5 – 10% (w/w) of liquid

compounds can be incorporated into polyethylene

glycol6000 without significant loss of its solid property

[49]. It is possible that the selected solvent or dissolved

drug may not be miscible with the melt of the

polyethylene glycol. Also, the liquid solvent used may

affect the polymorphic form of the drug, which

precipitates as the solid dispersion. This technique

possesses unique advantages of both the fusion and

solvent evaporation methods. From a practical

standpoint, it is only limited to drugs with a low

therapeutic dose e.g. below 50 mg.

5. Kneading technique

Drug and carrier weighed, they are combined, utilize

motor and pestle to diminish the size of the both drug

and carrier. Water-methanol blend 3:1 proportion was

added to the above mixture.The arrangement was

blended well and slurry was gathered by filtration and

dried in hot air oven for 2hrs at 5000C. Then dried mass

was gathered additionally dried in desiccated for

12hrs.Then the solid dispersion went to sieve no:80 to

get uniform molecule size [50].

6. Direct capsule filling:

Direct filling of hard gelatine capsules with the liquid

melt of solid dispersions avoids grinding-induced

changes in the crystallinity of the drug [51]. This molten

dispersion forms a solid plug inside the capsule on

cooling to room temperature, reducing cross

contamination and operator exposure in a dust-free

environment, better fill weight and content uniformity

was obtained than with the powder-fill technique.

24


However, PEG was not a suitable carrier for the direct

capsule-filling method as the water-soluble carrier

dissolved more rapidly than the drug, resulting in drug-

rich layers formed over the surface of dissolving plugs,

which prevented further dissolution of the drug [52].

7. Melt agglomeration method

This technique has been used to prepare SD wherein

thebinder acts as a carrier. In addition, SD(s) are

prepared either by heating binder, drug and

excipient to a temperature above the melting point of

the binder (melt-in procedure) or by spraying a

dispersion of drug in moltenbinder on the heated

excipient (spray-on procedure) byusing a high shear

mixer [53]. A rotary processor has been shown to be

alternative equipment for melt agglomeration. The rotary

processor might be preferable to the high melt

agglomeration because it is easier to control

the temperature and because a higher binder content can

beincorporated in the agglomerates [54]. The effect of

binder type, method of manufacturing and particle size

are critical parameters in preparation of SD(s) by melt

agglomeration. Since these parameters result in

variations in dissolutionrates, mechanism of agglomerate

formation and growth, agglomerate size, agglomerate

size distribution and densification of agglomerates. It

has been investigated that the melt in procedure givesa

higher dissolution rates than the spray-on procedure with

PEG3000, poloxamer 188and gelucire 50/13 attributed to

immersion mechanism of agglomerate formation and

growth. In addition, the melt in procedure also results in

homogenous distribution of drug in agglomerate. Larger

particles result in densification of agglomerates while

fineparticle cause complete adhesion to the mass to bowl

shortly after melting attributed to distribution and

coalescence of the fine particles [55].

8. Dropping method

The dropping method facilitate the crystallization of

different chemicals and produces round particles from

melted solid dispersions. In laboratory-scale preparation,

a solid dispersion of a melted drug-carrier mixture is

pipetted and then dropped onto a plate, where it solidifies

into round particles. The size and shape of the particles

can be influenced by factors such as the viscosity of the

melt and the size of the pipette. Because viscosity is

highly temperature-dependent, it is very important to

adjust the temperature so that when the melt is dropped

onto the plate it solidifies to a spherical shape. The use of

carriers that solidify at room temperature may aid the

dropping process. The dropping method not only

simplifies the manufacturing process, but also gives a

higher dissolution rate [56]. It does not use organic

solvents and, therefore, has none of the problems

associated with solvent evaporation. The method also

avoids the pulverization, sifting and compressibility

difficulties encountered with the other melt methods.

Disadvantages of the dropping method are that only

thermostable drugs can be used and the physical

instability of solid dispersions is a further challenge [57].

9. Supercritical fluid method

Supercritical fluid method generally uses supercritical

carbon dioxide (CO2) as a solubilizing solvent or anti-

solvent. When supercritical carbon dioxide is utilized as

a solvent, this method is considered an environmentally

friendly technique because no organic solvent is

required. Supercritical fluids are fluids whose

temperature and pressure are above the critical point. The

favourable properties of gases such as high diffusivity,

low surface tension and low viscosity imparted to liquids

through manipulation of the pressure of super critical

fluids allow the precise control of the solubilization of

many drugs. When using CO2 as a solvent, the drug and

carrier are dissolved in supercritical CO2 and sprayed

through a nozzle into an expansion vessel with lower

pressure. The rapid expansion induces rapid nucleation

of the dissolved drugs and carriers, leading to the

formation of solid dispersion particles with a desirable

size distribution in a very short time [58-60].

10. Lyophillization Techniques

Lyophilization has been thought of a molecular mixing

technique where the drug and carrier are co dissolved in

a common solvent, frozen and sublimed to obtain a

lyophilized molecular dispersion. This technique was

proposed as an alternative technique to solvent

evaporation. The advantages of freeze drying is that the

drug is subjected to minimal thermal stress during the

formation of the solid dispersion and the risk of phase

separation is minimized as soon as the solution is

vitrified. An even more promising drying technique is

25


spray-freeze drying. The solvent is sprayed into liquid

nitrogen or cold dry air and the frozen droplets are

subsequently lyophilized. The large surface area and

direct contact with the cooling agent results in even

faster vitrification, thereby decreasing the risk for phase

separation to a minimum. Moreover, spray freeze drying

offers the potential to customize the size of the particle to

make them suitable for further processing or applications

like pulmonary or nasal administration [61-62].

11. Spray-Drying method

Spray drying is an efficient technology for solid

dispersion manufacturing because it permits extremely

rapid solvent evaporation resulting in fast transformation

of an API-carrier solution to solid API-carrier particles.

In this technique, the API-carrier solution or suspension

is transported from the container to the nozzle entrance

via a pump system and atomized into fine droplets with

large specific surface area. These droplets result in rapid

evaporation of the solvent and the formation of solid

dispersions within seconds. The size of the solid

dispersion particles prepared by spray drying can be

customized by modulating the droplet size via nozzle to

meet the requirements for further processing or

applications. The drugs in solid dispersions prepared by

spray drying are often in amorphous state; therefore, the

solubility and dissolution rate are significantly increased.

Spray drying is one of the most common techniques used

to prepare solid dispersions due to the possibility of

continuous manufacturing, ease of scalability, good

uniformity of molecular dispersion and cost-

effectiveness in large scale production with high

recoveries (more than 95%) [63-66].

12. Gel entrapment technique

Hydroxyl propyl methyl cellulose is dissolved in organic

solvent to form a clear and transparent gel. Then drug for

example is dissolved in gel by sonication for few

minutes. Organic solvent is evaporated under vacuum.

Solid dispersions are reduced in size by mortar and

sieved [67].

13. Co-precipitation method

Co-precipitation is a suitable technique to prepare solid

dispersions of poorly water-soluble drugs which have

low solubility in commonly used organic solvents and

high melting points that can not be processed by melting

and other solvent methods [68]. In this method, a drug

and carrier are completely dissolved in an organic

solvent before adding to an anti-solvent which causes

simultaneous precipitation of the drug and carrier. The

resulting suspension is then filtered and washed to

remove residual solvents. The co-precipitated material

obtained after filtration and drying is referred to

microprecipitated bulk powder (MPD) which is a solid

dispersion of the drug and carrier [129]. The polymers

used in co-precipitation method often have pH dependent

solubility such as polymethylacrylate,

polymethylmethacrylate, HPMCP, HPMCAS, polyvinyl

phthalate and cellulose acetate phthalate while some

solvents such as dimethylacetamide, dimethylformamide

and N-methyl pyrrolidone are mainly used due to their

excellent solvency power, particularly for high molecular

weight polymers [69].

14. Co-grinding method

Physical mixture of drug and carrier is mixed for some

time employing a blender at a particular speed. The

mixture is then charged into the chamber of a vibration

ball mill steel balls are added. The powder mixture is

pulverized. Then the sample is collected and kept at

room temperature in a screw capped glass vial until use.

Ex. chlordiazepoxide solid dispersion was prepared by

this method [70].

15. Electro spinning method.

Electrospinning is a process in which solid fibers are

produced from a polymeric fluid stream solution or melt

delivered through a millimetre-scale nozzle. This process

involves the application of a strong electrostatic field

over a conductive capillary attaching to a reservoir

containing a polymer solution or melt and a conductive

collection screen. Upon increasing the electrostatic field

strength up to but not exceeding a critical value, charge

species accumulated on the surface of a pendant drop

destabilize the hemispherical shape into a conical shape

(commonly known as Tayloscone). Beyond the critical

value, a charged polymer jet is ejected from the apex of

the cone (as a way of relieving the charge built-up on the

surface of the pendant drop). The ejected charged jet is

then carried to the collection screen via the electrostatic

26


force. The Coulombic repulsion force is

responsible for the thinning of the charged jet during its

trajectory to the collection screen. The thinning down of

the charged jet is limited by the viscosity increase, as the

charged jet is dried[71].This technique has tremendous

potential for the preparation of nanofibers and

controlling the release of biomedicine, as it is

simplest,the cheapest[72] this technique can be utilized

for the preparation of solid dispersions in future.

16. Use of Surfactant

The utility of the surfactant systems in solubilization is

well known. Adsorption of surfactant on solid surface

can modify their hydrophobisity, surface chargeand other

key properties that govern interfacial processes

such as flocculation/dispersion, floatation, wetting,

solubilization, detergency, enhanced oil recovery

and corrosion inhibition. Surfactants have also been

reported to cause solvation/plasticization, manifesting

in reduction of melting the active pharmaceutical

ingredients, glass transition temperature and the

combined glass transition temperature of solid

dispersions. Because of these unique

properties,surfactants have attracted the attention

of investigators for preparation of solid dispersions [73].

Advantages of Solid Dispersions[74]

1. Improving drug bioavailability by changing their water

solubility has been possible by solid dispersion.

2. Solid dispersions are more efficient than these particle

size reduction techniques, since the latter have a particle

size reduction limit around 2-5 mm which frequently is

not enough to improve considerably the drug solubility

or drug release in the small intestine.

3. Increase in dissolution rate & extent of absorption and

reduction in Pre systemic metabolism.

4. Transformation of liquid form of drug into solid form.

5. Parameters, such as carrier molecular weight and

composition, drug crystallinity and particle porosity and

wettability, when successfully controlled, can produce

improvements in bioavailability

Disadvantages of Solid Dispersions

1. Most of the polymers used in solid dispersions can

absorb moisture, which may result in phase separation,

crystal growth or conversion from the amorphous to the

crystalline state or from a metastable crystalline form to

a more stable structure during storage. This may result in

decreased solubility and dissolution rate.

2. Drawback of solid dispersions is their poor scale-up for

the purposes of manufacturing.

Characterization of Solid Dispersion

Many methods are available that can contribute

information regarding the physical nature of solid

dispersion system. A combination of two or more

methods is required to study its complete picture [75].

1) Thermal analysis.

2) Spectroscopic method.

3) X-ray diffraction method.

4) Dissolution rate method.

5) Microscopic method.

6) Thermodynamic method.

7) Modulated temperature differential scanning

calorimetry

8) Environmental scanning electron microscopy

9) Dissolution testing

Applications of Solid Dispersions[76]

Aside from absorption improvement, the solid dispersion

procedure may have various pharmaceutical applications,

which ought to be additionally investigated.

To obtain a homogeneous distribution of a small

amount of drug in solid state.

To stabilize the unstable drug.

To dispense liquid or gaseous compounds in a solid

dosage.

To formulate a fast release primary dose in a

sustained released dosage form.

To formulate sustained release regimen of soluble

drugs by using poorly soluble orinsoluble carriers.

To reduce pre systemic inactivation of drugs like

morphine and progesterone. Polymorphsin a given

system can be converted into isomorphism, solid

solution, eutectic or molecular compounds.

27


To increase the solubility of poorly soluble drugs

thereby increase the dissolution rate, absorption and

bioavailability.

To stabilize unstable drugs against hydrolysis,

oxidation, recrimination, isomerisation, photo

oxidation and other decomposition procedures.

To reduce side effect of certain drugs.

Masking of unpleasant taste and smell of drugs.

Improvement of drug release from ointment, creams

and gels.

To avoid undesirable incompatibilities.

To obtain a homogeneous distribution of a small

amount of drug in solid state.

To dispense liquid (up to 10%) or gaseous

compounds in a solid dosage.

To formulate a fast release primary dose in a

sustained released dosage form.

To formulate sustained release regimen of soluble

drugs by using poorly soluble or insoluble carriers.

To reduce pre systemic inactivation of drugs like

morphine and progesterone.

Recent Development and Future Trends

Solid dispersions have generated a great deal of interest

from pharmaceutical scientists due to the increasing

number of drug candidates which is poorly water soluble

and the recent advances in this field. Although solid

dispersions have been studied for so long, some novel

carriers, additives and new preparation, characterization

techniques have just been applied in recent years. This

brings new hope for the future developmentof more solid

dispersion products. Recent advances on solid dispersion

area can be divided into four main issues: (i) applying

new carriers, (ii) adding new additives such as

surfactants, super disintegrates and pH modifiers, (iii)

developing novel preparation and characterization

methods, (iv) elucidating the thermodynamic mechanism

of many processes in the preparation, formulation,

dissolution and storage stage. These issues are

interrelated and will be continuously investigated in the

coming time.

CONCLUSION

Solubility is a most important criterion for the oral bio

availability of poorly soluble drugs. Drug dissolution is

the rate that determines the oral absorption of the poorly

aqueous-soluble drugs, which may subsequently affect

the in vivo absorption of drug. Currently only 8% of new

drug candidates actually have both high solubility and

permeability. Due to the problem of solubility of many

medications, their bio-availability is impaired and

therefore the enhancement in solubility becomes

necessary. Solid dispersion technology is one of the

potential ways of increasing the solubility of drugs which

are poorly water soluble. The various technologies

discussed have been successful in the laboratory and the

scale-up. Some products have been marketed using

technologies like the surface-active carriers. As a result,

these technologies are likely to form a basis for the

marketing of many poorly water-soluble and water-

insoluble drugs in their solid-dispersion formulations in

the near future. Solid dispersions that increase

dissolution rate of drugs with poor water-solubility, but

stability of these systems needs to be taken in to account

and the drug carriers need to be chosen on a case by case

basis. Solvent systems consisting of solvent mixtures can

be used to optimize concentration in solution processing

parameters which affect the type of glass amorphous

system formed.

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1. J.A. Baird, L.S. Taylor, Evaluation of

amorphous solid dispersion properties using

thermal analysis techniques, Adv. Drug

Delivery Rev. 64 (2012) 396– 1312 421.

2. C.A. Lipinski, F. Lombardo, B.W. Dominy, P.J.

Feeney, Experimental and computational

approaches to estimate solubility and

permeability in drug discovery and development

settings, Adv. Drug Delivery Rev. 46 (2012) 3–

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