See discussions, stats, and author profiles for this publication at: [Link]
net/publication/303408430
TERNARY SOLID DISPERSIONS OF OMEPRAZOLE FOR ENHANCING
SOLUBILITY AND DISSOLUTION
Article in World Journal of Pharmaceutical Research · January 2015
CITATIONS READS
2 3,138
2 authors, including:
Arshad Khan
Creative Educational Society’s College of Pharmacy
33 PUBLICATIONS 104 CITATIONS
SEE PROFILE
All content following this page was uploaded by Arshad Khan on 23 May 2016.
The user has requested enhancement of the downloaded file.
World Journal of Pharmaceutical Research
Ahmed et al. World Journal of Pharmaceutical Research
SJIF Impact Factor 5.990
Volume 4, Issue 10, 2402-2412. Research Article ISSN 2277– 7105
TERNARY SOLID DISPERSIONS OF OMEPRAZOLE FOR
ENHANCING SOLUBILITY AND DISSOLUTION.
Arshad Ahmed Khan K.*1, Aparna.P1, Harathi.P1, Padmanabha Reddy.Y2, Sowmya.C1
1
Department of Pharmaceutics, Center for Pharmaceutical Research (CPR), Raghavendra
Institute of Pharmaceutical Education and Research [RIPER], Anantapur, Andhra Pradesh-
515 921, India.
2
Department of Pharmaceutical Analysis, Center for Pharmaceutical Research (CPR),
Raghavendra Institute of Pharmaceutical Education and Research [RIPER], Anantapur,
Andhra Pradesh-515 921, India
ABSTRACT
Article Received on
12 Aug 2015, Omeprazole, is widely used in the treatment of acid, peptic disorders
Revised on 06 Sept 2015, and duodenal ulcers. One of the major problems with this drug is its
Accepted on 27 Sept 2015,
low solubility in biological fluids, which results into poor
bioavailability after oral administration. Therefore to increase its
*Correspondence for aqueous solubility ternary solid dispersions (TSD) of omeprazole were
Author
prepared by solvent evaporation method, using hydrophilic carriers
Arshad Ahmed Khan K.
like polyvinyl pyrrolidone (PVP), hydroxyl propyl methyl cellulose
Department of
Pharmaceutics, Center for
(HPMC), and solubilizer sodium lauryl sulphate (SLS). Eight formulae
Pharmaceutical Research were prepared and evaluated for drug content, solubility, In‐vitro drug
(CPR), Raghavendra release and dissolution efficiency. Solid state characterization
Institute of Pharmaceutical
including FTIR and XRD is also carried out. All formulae showed
Education and Research
marked significant improvement in the solubility and dissolution rate
[RIPER], Anantapur,
Andhra Pradesh-515 921, of the drug. Solubility studies indicated that PVP along with SLS
India. significantly increased the solubility as well as the bioavailability of
omeprazole by 14.66 folds. The interaction studies showed no
interaction between the drug and any of the used carriers. In‐vitro release profiles of all
dispersions were comparatively evaluated and also studied against pure omeprazole. Faster
dissolution with greater dissolution efficiency was exhibited by ternary solid dispersion (F7)
containing omeprazole: PVP: SLS in 1:1:0.75 ratios. The cumulative release of omeprazole
from formulation F7 was 98.15% within 60 min and was 4.48 times higher than the pure drug
[Link] Vol 4, Issue 10, 2015. 2402
Ahmed et al. World Journal of Pharmaceutical Research
in 0.1N HCl. The increase in dissolution rate of omeprazole by ternary dispersion technique
may be due to increase wettability and hydrophilic nature of carrier.
KEYWORDS: Omeprazole, ternary solid dispersion, solvent evaporation method, Solubility.
INTRODUCTION
A large percentage of potential drug candidates suffer from low aqueous solubility and/or low
dissolution rate. This results in low drug concentrations at the absorptive sites and hence low
oral availability. Amidon et al. classified such drugs in the biopharmaceutical classification
system as class II compounds. The formulation of solid dispersions of BCS II compounds
either by co-precipitation of drug and carrier from a common solvent or by co melting and
quench cooling is a popular strategy to reduce the drug particle size and hence increases
dissolution rate.[1] The dissolution rate is affected by state and size of the particle and carrier
with in which it is enclosed. Small size of the drug particles cause increased surface area
which helps in enhancement of drug dissolution. Amorphous state of the drugs increased
solubility of the drug and hydrophilic carrier enhances wetting characteristics of the drugs
which ultimately leads to increased dissolution rate of drugs in solid dispersions.[2] But solid
dispersions have disadvantages like phase separation, crystal growth or conversion from the
amorphous to the crystalline state during storage inevitably leading to reduced dissolution
rates.[3]
Surfactants lower the interfacial tension between a drug and the dissolution medium and there
by promote wetting of a drug. The addition of surfactants in solid dispersions leads to the
formation of a ternary system, called Ternary solid dispersions (TSD) which enhances the
solubility and dissolution of poorly soluble drugs. Ternary solid dispersions are defined as the
dispersion of active ingredients in an inert carrier matrix of surfactant and polymers. In TSD
carriers reduce molecular mobility and prevent recrystallization. Moreover hydrophillic
polymers are able to enhance drug super saturation, surfactant decrease aggregation, improve
wetting, and increases dissolution of drug.[4,5] Polyvinyl pyrrolidone has been widely used as
a carrier for solid dispersions of drugs such as furosemide.[6] oxaprozin[7] nimodipine.[8] and
albendazole.[9] Hydroxypropylmethylcellulose as a carrier enhanced enhanced solubility and
bioavailability of various drugs like itraconazole.[10] sibutramine.[11] and curcumin.[12]
Omeprazole is a proton pump inhibitor that suppresses gastric acid secretion by specific
inhibition of the H+/K+- ATPase in the gastric parietal cell. By acting specifically on the
proton pumpomeprazole blocks the final step in acid production.[13] The drug is used in
[Link] Vol 4, Issue 10, 2015. 2403
Ahmed et al. World Journal of Pharmaceutical Research
conditions where the inhibition of gastric acid secretion may be beneficial, including
aspiration syndromes, dyspepsia, gastro-oesophageal reflux disease, peptic ulcer disease, and
the Zollinger Ellison syndrome.[14] But it does not show comprehensive therapeutic effect
because of its poor solubility and dissolution, which leads to poor bioavailability of the drug.
In the present investigation TSD of omeprazole were prepared by physical mixture and
solvent evaporation method, employing various carriers like polyvinyl pyrrolidone (PVP
K25), hydroxyl propyl methyl cellulose (HPMC 15cps), and sodium lauryl sulphate (SLS) as
surfactant for enhancing the solubility and dissolution rate.
MATERIALS AND METHODS
Materials
Omeprazole was obtained as a gift sample from Bangalore fine chemicals, India. Polyvinyl
pyrrolidone (PVP K25), hydroxyl propyl methyl cellulose (HPMC15cps), and sodium lauryl
sulphate (SLS) were obtained from lobachem. Pvt Ltd., SD fine chem. ltd., and fisher
scientific, Mumbai, India respectively. All other chemicals and solvents were of analytical
grade.
METHODS
Preparation of omeprazole TSD
Ternary dispersions of omeprazole in were prepared using like PVP, HPMC as carriers and
SLS as ternary agent. In formulations ratio of drug: carrier was maintained in constant ratio
of 1:1 and SLS concentration was varied as shown in Table 1. The methods used for
preparation of these dispersions were physical mixing and solvent evaporation methods.
Table 1: Formulation table of omeprazole ternary solid dispersions.
Formulation code Omeprazole SLS HPMC (15cps) PVP K25
F1 1gm 25mg 1gm -
F2 1gm 50mg 1gm -
F3 1gm 95mg 1gm -
F4 1gm - 1gm -
F5 1gm 25mg - 1gm
F6 1gm 50mg - 1gm
F7 1gm 95mg - 1gm
8 1gm - - 1gm
[Link] Vol 4, Issue 10, 2015. 2404
Ahmed et al. World Journal of Pharmaceutical Research
Physical mixture
The physical mixtures were prepared by weighing the calculated amounts of omeprazole,
carriers and SLS, then mixing them in a glass mortar by triturating. The resultant physical
mixtures were passed through 44‐mesh sieve and stored in desiccator until used for further
studies.
Solvent evaporation method
omeprazole and carriers were dissolved separately in minimum quantity of acetone, mixed.
Ternary agent SLS was dispersed in the solution. The solution was evaporated on temperature
controlled water bath to get the solid mass which was then passed through sieve no.44 and
stored till further evaluations.
Saturation solubility study: Solubility study was conducted as per the method reported by
Higuchi and Connors. Excess quantity of the drug and TSD were taken for study. The
solubility of omeprazole in pure drug and TSD was determined in 0.1N Hcl. Drug and TSD
were weighed accurately and added to solvents in screw capped bottles separately. The
bottles were shaken in an orbital shaker at 37 0C for 24 hrs. The sample was then filtered
through Whatman filter paper and the filtrate was assayed spectrophotometrically at 281
nm.[15]
Drug content: TSD 50 mg was accurately weighed and dissolved in 100ml of buffer (0.1N
Hcl) and filtered. Filtered solution was suitably diluted and absorbance was measured with a
UV-visible spectrophotometer (Pharmaspec 1700, Shimadzu, Japan) at 281 nm.
Solubility studies: Solubility study was conducted as per the method reported Higuchi and
Connors. Excess quantity omeprazole TSD and physical mixtures were weighed accurately
and added to 10ml of in water and 0.1N Hcl in screw capped bottles. The bottles were shaken
in an orbital shaker at 37 0C for 24 hrs. Then the solutions were filtered, and concentration of
drug was determined by UV-visible spectrophotometer at 281 nm.
In-vitro dissolution studies: Omeprazole pure drug, physical mixtures and TSD equivalent
to 20 mg omeprazole were subjected to in-vitro dissolution studies using USP Dissolution
test apparatus II (paddle type) at 37±0.50C using 900ml 0.1N Hcl as dissolution media. The
rotation speed of the paddle was adjusted to 50rpm. Samples were collected at 5, 10, 20, 30,
45 and 60 minutes, passed through a 0.45µm filter and analyzed by direct UV visible
[Link] Vol 4, Issue 10, 2015. 2405
Ahmed et al. World Journal of Pharmaceutical Research
spectrophotometer at 281nm. Each preparation was tested in triplicate and the mean values
were calculated. The cumulative drug release was calculated and plotted versus time.[16]
Model Independent Approaches
(a) Dissolution Efficiency: Dissolution efficiency (DE) represents the area under the
dissolution curve at time t (measured using the trapezoidal rule) and expressed as
percentage of the area of the rectangle described by100 % dissolution in the same time.[17]
Where y is the drug percent dissolved at time t
(b) Initial dissolution rate (%/min)
To compare dissolution rate enhancement of omeprazole from TSDs formulae, Initial
dissolution rate (IDR) was calculated as percentage dissolved of drug over the first 5 minutes
per minute.[17]
FTIR: FTIR was used to access interaction between drug and carrier molecules used in
formulation. The IR spectra were recorded using a FTIR spectrophotometer. The moisture
free samples were scanned over the frequency range of 4000 to 400cm.-1 FTIR spectra of
selected formulation and physical mixtures were recorded.
X-ray diffraction (XRPD)
The crystallinity of Omeprazole pure drug, physical mixtures and TSD was investigated by
XRPD using Bruker diffractometer (WI 1140, Japan) and Cu-Kα radiation. The
diffractograms were run at 2.5 °C min-1 and chart speed of 2°/2 cm per 2θ angle.
RESULTS AND DISCUSSION
Solubility studies: Table 2 summarizes the experimentally determined solubility of
omeprazole, and its TSDs in 0.1N Hcl. With a solubility of 0.15mg/ml (at 37oc), omeprazole
is clearly poorly soluble. TSD prepared by solvent evaporation method with incorporation of
HPMC, PVP along with SLS as ternary agent showed solubility enhancement up to
1.86mg/ml, and 2.28 mg/ml respectively. Solubility was also found to increase in biorelevant
media as they contain hydrophilic polymers and SLS. The surfactant is likely to exert
micellar solublization effect on the omeprazole. In formulation F7 the omeprazole solubility
[Link] Vol 4, Issue 10, 2015. 2406
Ahmed et al. World Journal of Pharmaceutical Research
increased by 14.66 folds. The combined effect of hydrophilic polymers and SLS in the TSD
has produced significant enhancement in the solubility of omeprazole. The mechanism for
solubility enhancement by TSD is reported because of increased surface area due to reduction
in particle size of drug and wetting, solublizing effect of the carrier.
Drug content: The drug content in was found to be in the range of 99-97% in formulations
F1-F4 containing HPMC, it was 100-98% in formulation F5-F8 containing PVP as shown in
table 2. The results indicate high content uniformity in the omeprazole TSD.
Table 2: Results of solubility and drug content of omeprazole TSD
Formulation Solubility (mg/ml) % Increase Drug content average
code in 0.1N Hcl (average ±S.D) in solubility (% ± S.D)
F1 1.266 ±0.24 844 98.199±0.13
F2 1.630 ±0.25 1086.6 98. 996 ±0.86
F3 1.861±0.08 1240.6 99.599±0.22
F4 1.194 ±0.24 996 97.643±0.91
F5 1.354 ±0.36 902.6 98. 981±0.05
F6 1.863 ±0.29 1242 99.196±0.88
F7 2.280 ±0.26 1520 100.692±0.15
F8 1.296 ±0.36 864 99.292±0.81
Pure omperazole 0.15±0.08 ----- ------
In-vitro dissolution studies
The dissolution profiles of omeprazole, physical mixtures and TSD prepared with hydrophilic
polymers and surfactant were determined in 0.1N HCL. The release profiles were plotted as
the percentage drug dissolved versus time. From release profile plots it is evident that the rate
of dissolution of pure omeprazole in 0.1N HCL was slow and showed release of 21.89%
within 60 min. Formulation F1-F4 containing HPMC as a carrier showed drug release in the
range of 93-74.4% in 60min. Formulation F5-F8 PVP as a carrier showed drug release in the
range of 98.15-80.14% in 60 min. Among all formulations F1-F8 best formulation were
selected for each carrier basing on maximum drug release within 60 min. The best
formulations are F3 (93% drug release) containing HPMC, and F9 (98.15% drug release)
containing PVP. The drug dissolution in formulations increased with gradual increase in
amount of surfactant SLS. Physical mixtures of best formulations PM 3 released 53.88% and
PM 7 released 58.57% in 60 min. Figures 1& 2 shows the dissolution profiles of pure
omeprazole and its physical mixtures and TSD respectively.
[Link] Vol 4, Issue 10, 2015. 2407
Ahmed et al. World Journal of Pharmaceutical Research
Hence, the TSD prepared by solvent evaporation method showed faster release of omeprazole
compared to dispersion obtained by physical mixture technique. This may be due to the fact
that ternary dispersion prepared by solvent evaporation method result in a more uniform
dispersion of the drug in the hydrophilic carriers (PVP) matrix as compared to those prepared
by physical mixture technique.
The increase in dissolution from the solid dispersion was due to the solublizing effect of the
carrier, which forms a hydrophilic interfacial layer between the drug particles and the
dissolution medium, thus leading to a higher dissolution rate. When solid dispersion
consisting of an insoluble drug and a highly water soluble carrier with surfactants was
dissolved in aqueous medium, the carrier would dissolve rapidly, leaving the insoluble drug
in an extremely fine state of subdivision. The large surface area of the resulting suspended
particles might have resulted in an enhanced dissolution rate and improved bioavailability.
Figure 1: Dissolution profiles of omeprazole TSD prepared by physical mixture method.
Figure 2: Dissolution profiles of omeprazole TSD prepared by solvent evaporation
method
[Link] Vol 4, Issue 10, 2015. 2408
Ahmed et al. World Journal of Pharmaceutical Research
Model Independent Approaches
The calculated %DE5min, %DE30min, %DE60min and IDR values are presented in table 3. The
average percentage release of pure drug was 21.87% in 60 min and it is obvious from %DE
30min of 14.65 and IDR of 0.72 %/min that the dissolution of pure omeprazole is poor and
slow and this was attributed to the hydrophobicity of the drug. Formulation of omeprazole as
ternary solid dispersion with either HPMC or PVP resulted in significant enhancement of
omeprazole dissolution and this is clear from the values of %DE5min, %DE30min, %DE60min and
IDR compared to the pure drug (table 3). The results obtained revealed that all ternary solid
dispersions of omeprazole have faster dissolution than pure omeprazole. Of note is the fact
that the extent of enhanced dissolution depended on the concentration of the polymer used in
the solid dispersion, increasing the polymer concentration leaded to increasing the drug
release. Formulae prepared with PVP showed higher dissolution rates than those prepared
with HPMC and this may be explained as the PVP produced less viscous dispersion and the
rapid diffusion of the dissolved drug molecules.
Table 3: Dissolution parameters obtained from dissolution data of different TSD
formulae.
Formulation Dissolution Parameters
code %DE5min %DE30min %DE60min IDR(%/min)
Pure drug 3.6±0.08 14.65±0.41 21.87±0.21 0.72±0.25
F1 4.83±0.05 59.3±0.23 80.05±0.54 0.97±0.36
F2 7±0.02 62.05±0.58 83.09±0.2 1.40±0.15
F3 8.92±0.12 74.4±0.61 93±0.65 1.78±0.2
F4 9.14±0.16 55.8±0.35 74.4±0.81 1.83±0.6
F5 8.31±0.09 46.68±0.71 80.14±0.51 1.66±0.8
F6 8±0.054 67.88±0.84 91.98±0.21 1.60±0.51
F7 11.59±0.02 77.05±0.21 98.15±0.16 2.32±0.16
F8 7.08±0.025 58.76±0.19 74.96±0.54 1.42±0.21
FTIR spectroscopy data
The FTIR spectrum of pure drug, TSD best formulation F7 and its PM 7 are presented in
figure 3(a, b, c) respectively. Pure drug shown sharp characteristic bands at 3352, 125 9,
1620, 2921,119 9cm-1 due to stretching vibration bands of N-H, S=O, C=N, C-H, O-C
respectively. FTIR spectra of the F 7 and PM 7 show the characteristic bands of the drug with
negligible change in intensity and this may be due to the dilution factor of the mixture by the
carrier. The FTIR study revealed no physical or chemical interactions of omeprazole with
PVP and SLS.
[Link] Vol 4, Issue 10, 2015. 2409
Ahmed et al. World Journal of Pharmaceutical Research
Figure 3: FTIR spectra of (a) pure omeprazole, (b) PM 7, (c) TSD best formulation F7.
XRPD Studies: The X-Ray diffraction pattern for omeprazole and TSD are depicted in
Figure 4 and showed marked crystallinity as evident from the sharp peaks at 2θ angles of
9.12º, 12.4º, 1 9.34º and 23.98º. The degree of crystallinity is seen to be decreased and it
depends on the processing method. The XRPD of TSD prepared by physical mixture shows
higher degree of crystallinity as compared to those prepared by solvent evaporation method
as evident from the disappearance of the sharp peaks. This could be attributed to the rapid
evaporation of solvent from the solution seemingly interferes with the crystal building
process leading to amorphization of the drug, consequently increased the drug solubility.
Figure 4: XPRD spectra of (a) pure omeprazole, (b) PM 7, (c) TSD best formulation F7.
[Link] Vol 4, Issue 10, 2015. 2410
Ahmed et al. World Journal of Pharmaceutical Research
CONCLUSION
TSDs of omeprazole prepared by solvent evaporation method possessed dramatically higher
solubility & dissolution rates as compared to pure omeprazole and dispersions prepared by
physical mixture method. The FTIR study indicated no chemical interaction between drug
and excipients. The intermolecular interactions between drug and carriers leading to better
dispersion of drug in the polymer matrix, reduction in size of drug particles, increase in the
amorphous nature, increase in wettablity and decrease in surface tension resulted in enhanced
dissolution of the drug from the ternary dispersion system. PVP K25 along with SLS exerted
synergistic effect to enhance solubility as well as dissolution of poorly soluble omeprazole
drug.
ACKNOWLEDGMENT
The authors are very thankful to Bangalore fine chemicals for providing a gift sample of
omeprazole and Centre of Pharmaceutical Research of Raghavendra Institute of
Pharmaceutical Education & Research (RIPER), Anantapur, Andhra Pradesh for providing
suitable facilities for this research work.
REFERENCES
1. Sandrien J ,Sophie N, Hector N d A, Ward D A, Ann V S, Guy V d M. Formulation and
characterization of ternary solid dispersions made up of Itraconazole and two excipients,
TPGS 1000 and PVPVA 64, that were selected based on supersaturation screening study.
European journal of pharmaceutics and biopharmaceutics, 2009; 1-9.
2. Kadir M F, Sayeed S B, Khan R I, Shams T and Islam M d S. Study of binary and ternary
solid dispersion of ibuprofen for the enhancement of oral bioavailability. Journal of
applied pharmaceutical science, 2011; 01(09): 103-109.
3. Jagadeesan R, Radhakrishnan M. Novel approaches in the preparation of solid dispersion
on solubility: A review. Int J Pharm Sci, 2013; 5(3): 1000-1004.
4. Aejaz A, Jafar M, Dehghan. MHG, Adil shareef S. Meloxicam-PVP-SLS Ternary
dispersion systems: in vitro and in vivo evaluation. International of pharmacy and
pharmaceutical sciences, 2010; 2(1): 182-190.
5. Patel DM, Patel SP, Patel CN. Formulation and evaluation of fast dissolving tablet
containing domperidone ternary solid dispersion. Int J Pharma investing, 2014; 4(4): 194-
182.
[Link] Vol 4, Issue 10, 2015. 2411
Ahmed et al. World Journal of Pharmaceutical Research
6. Ak buga J. Effect of Additives on dissolution characteristics of furosemide – polyvinyl
pyrrolidone solid – dispersion systems. Pharm Ind, 1991; 53(9): 859‐860.
7. Tanabe K, Itoh S, Iwasakit, Nakano Y, Yamazaki M. Rectal absorption enhancement of
Oxaprozin using solid dispersions with polyvinyl pyrrolidone. Jpn J Hosp pharm, 1994;
20(6): 509‐514.
8. Chowdary KP, Murthy KV, Prasad CD. Solid dispersion of Nimodipine; physicochemical
and Dissolution rate studies. Indian Drugs, 1995; 32: 539–542.
9. Torrado S, Torrado JJ, cadorniga R. preparation, dissolution and characterization of
Albendazole Solid Dispersions. Int J pharmaceutics, 1996; 140 (2): 24 9‐ 250.
10. Six K, Daems T. Clinical study of solid dispersions of itraconazole prepared by hot-stage
extrusion. Eur J Pharm Sci, 2005; 24(23): 199-186.
11. Chul Soon Y. Development of novel sibutramine base-loaded solid dispersion with
gelatin and HPMC: Physicochemical characterization and pharmacokinetics in beagle
dogs. Int J Pharm, 2010; 399: 225-230.
12. Wolska E, Sznitowska M. Technology of stable, prolonged-release eye-drops containing
Cyclosporine A, distributed between lipid matrix and surface of the solid lipid
microspheres (SLM).Int J Pharm, 2012; 12: 1016-1018.
13. Prathyusha S, Prathima S, Arshad Ahmed khan K, Sowmya C. Formulation and
Evaluation of Omeprazole Buccoadhesive Tablets: Effect of Polymers. International
Journal of Research in Pharmacy and Life Sciences, 2013; 1(2): 84-91.
14. Satoshkar RS, Bhandarkar SD, Rege NN. Pharmacology and pharmacotherapeutics. 21 st
ed., Popular Prakashan, Mumbai, 2010; p119-121.
15. Bhise SD. Ternary solid dipersions of fenofibrate with poloxamer 188 and TPGS for
ebhancement of solubility and bioavailability. International journal of research in
pharmaceutical and biomedical sciences, 2011; 2(2): 2229-3901.
16. Nagabhushanam MV, Prasada rao V, Beena Devi M, Suresh kumar J. Ternary solid
dispersion of celecoxib: From physical characterization on dissolution enhancement.
Journal of pharmaceutical research, 2013; 12(2): 80-85.
17. Zaki M, Adel A, Shahira F, Ahmed abdel B. Effect of binary and ternary solid dispersions
prepared by fusion method on the dissolution of poorly water soluble diacerein.
International Journal of Drug Delivery, 2013; 5(1): 99-109.
[Link] Vol 4, Issue 10, 2015. 2412
View publication stats