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Online : ISSN 2349-669X
Print : ISSN 0973-9874 J.Pharm.Chem CODEN: JPCOCM
Journal of Pharmacy and Chemistry (An International Research Journal of Pharmaceutical and Chemical Sciences)
Indexed in Chemical Abstract and Index Copernicus (IC Value 5.28)
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Editorial Board
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October - December 2019 2 Journal of Pharmacy and Chemistry • Vol.13 • Issue.4
Online : ISSN 2349-669X
Print : ISSN 0973-9874 J.Pharm.Chem CODEN: JPCOCM
Journal of Pharmacy and Chemistry (An International Research Journal of Pharmaceutical and Chemical Sciences)
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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October - December 2019 3 Journal of Pharmacy and Chemistry • Vol.13 • Issue.4
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.
October - December 2019 4 Journal of Pharmacy and Chemistry • Vol.13 • Issue.4
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
October - December 2019 5 Journal of Pharmacy and Chemistry • Vol.13 • Issue.4
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.
October - December 2019 6 Journal of Pharmacy and Chemistry • Vol.13 • Issue.4
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
6-chloro-1,4-dihydro-
2-(3-hydroxy-4-
Cl methoxyphenyl)-N'-
phenylquinoline-4-
QC-2
OCH3
carbohydrazide
OH
O
C
NH NH
6-chloro-1,4-dihydro-
Cl 2-(3-methoxyphenyl)-
N'-phenylquinoline-4-
N
carbohydrazide
QC-3
OCH3
O
NH NH
6-chloro-1,4-dihydro-
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
October - December 2019 7 Journal of Pharmacy and Chemistry • Vol.13 • Issue.4
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.
October - December 2019 8 Journal of Pharmacy and Chemistry • Vol.13 • Issue.4
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
October - December 2019 9 Journal of Pharmacy and Chemistry • Vol.13 • Issue.4
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.
October - December 2019 10 Journal of Pharmacy and Chemistry • Vol.13 • Issue.4
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
October - December 2019 11 Journal of Pharmacy and Chemistry • Vol.13 • Issue.4
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.
October - December 2019 12 Journal of Pharmacy and Chemistry • Vol.13 • Issue.4
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
October - December 2019 13 Journal of Pharmacy and Chemistry • Vol.13 • Issue.4
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
October - December 2019 14 Journal of Pharmacy and Chemistry • Vol.13 • Issue.4
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.
October - December 2019 15 Journal of Pharmacy and Chemistry • Vol.13 • Issue.4
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
October - December 2019 16 Journal of Pharmacy and Chemistry • Vol.13 • Issue.4
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.
October - December 2019 17 Journal of Pharmacy and Chemistry • Vol.13 • Issue.4
January - March 2012 31 Journal of Pharmacy and Chemistry • Vol.6 • Issue.1
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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]
October-December 2019 20 Journal of Pharmacy and Chemistry . Vol. 13 . Issue.4
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
October-December 2019 21 Journal of Pharmacy and Chemistry . Vol. 13 . Issue.4
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
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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,
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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.
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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
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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
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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.
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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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