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Preparation of Freeze-dried Solid Dispersion Powder using Mannitol to Enhance

Solubility of Lovastatin and Development of Sustained Release Tablet Dosage
Form
Article · June 2014

DOI: 10.13140/2.1.4312.5769
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Columbia International Publishing
American Journal of Pharmaceutical Sciences and Nanotechnology
(2014) Vol. 1 No. 1 pp. 11-26
Research Article
Preparation of Freeze-dried Solid Dispersion Powder

using Mannitol to Enhance Solubility of Lovastatin and
Development of Sustained Release Tablet Dosage Form
UmakantVerma1, J. B. Naik1*and V.J. Mokale1
Received 23 January 2014; Published online 14 June 2014
© The author(s) 2014. Published with open access at www.uscip.us
Abstract
The Aim of the present study was to prepare Lovastatin (LOV) solid dispersion (SD) by bottom up process
based upon freeze drying and to incorporate this solid dispersion into sustained-release tablet dosage form.
Lovastatin having a short elimination half-life (1-2 hrs), low water solubility hence, low dissolution rate and
oral bioavailability. To increase the water solubility and dissolution rate of the LOV, solid dispersion was
prepared using different ratio of water/tertiary-butyl alcohol (TBA) as solvent and anti-solvent (co-solvent)
system for Mannitol and Lovastatin. Prepared SD was characterized for solubility, differential scanning
calorimetry (DSC), X- ray diffraction (X-RD), Fourier transform infrared spectroscopy (FTIR), FE-SEM and
Particle size distribution. DSC and XRD study showed partial interaction between the drug and carrier.
Further, to reduce the dosing frequency and side effect sustained-release tablet of LOV solid dispersion was
prepared by the Wet - granulation method using release retarding polymer HPMC K15 and Ethocel 20cps
alone or in combination. Drug release of optimized batch showed sustained releaseupto24 hrs and optimized
formulation follow first order kinetics. From the study, we can conclude that the developed LOV sustained-
release tablets could perform better release than conventional tablet, leading to improved patient
compliance.
Keywords: Lovastatin, Solid dispersion, Freeze drying, Solubility, Bioavailability, Release retarding polymers
1. Introduction
According to the Biopharmaceutical Classification System (BCS) many new drugs can be considered
as class II or Class IV drugs. BCS Class II drugs are poorly water soluble but once these drugs are
dissolved, they rapidly absorbed over the biological membranes such as the gastrointestinal tract.
After oral administration due to the poor aqueous solubility these drugs having a slow dissolution
_____________________________________________________________________________________________________________________________
*Corresponding e-mail: jitunaik@gmail.com
1* Department of Pharmaceutical Technology, University Institute of Chemical Technology, North 11
Maharashtra University, Umavi Nagar, Post Box No. 80, Jalgaon-425 001, Maharashtra, India.
Umakant Verma, J.B. Naik, and V.J. Mokale /
American Journal of Pharmaceutical Sciences and Nanotechnology (2014) Vol. 1 No. 1 pp. 11-26
rate in gastrointestinal tract result in low oral bioavailability(Visser et al., 2010; Lipinski et al.,
2012).Solubility is the key factor in determining the rate and extent of absorption of BCS class II
drugs (Jammula et al., 2013). Therefore increasing the solubility or dissolution rate of class II drugs
can improve the oral bioavailability (Wu et al., 2011; Wu et al., 2012; Curatolo, 1998).Several
techniques are used to increase the solubility of poorly water-soluble drugs and thus improve its
bioavailability such as (a) particle size reduction to increase surface area, (b) complexation with
cyclodextrin, (c) salt formation, (d) use of Prodrugs, (e) pH adjustment, (f) self- emulsifying
formulations, (g) use of surfactants and change in solid form such as nanocrystals, preparation of
liposome and solid dispersion. Solid dispersion is one of the approaches to increase the dissolution
rate of poorly water soluble drugs. Solid dispersion may be defined as dispersion of active
ingredientswithinan inert carrier in solid state (Bhowmiket al., 2012; Leuner and Dressman, 2000;
Kawabataet al.,2011; Chenet al.,2011). Solubility of LOV was increased by using solid dispersion
techniques (Patel et al., 2008; Shaikh et al, 2011). Solubility of LOV was also increasedby using
cyclodextrin complexation approach(Mehramizi et al, 2007).
The improvement of solubility and dissolution rate of drugs from solid dispersions is based on
mainly three different mechanisms include increased wettability of drug due to direct contact with
hydrophilic carrier, the reduction in particle size results increased surface area, and the conversion
of crystalline state to more soluble amorphous state (Waardet al.,2008). Solid dispersion is a viable
and economic method to enhance bioavailability of poorly water-soluble drugs and also overcomes
the limitations of the previous approaches (Maulvi et al., 2011). Numbers of strategies are used for
the preparation of nano sizeddrug particles, which are classified as bottom- up, top-down,
combination approaches and chemical synthesis. Most of the top-down process requires high
energy input where the drug particles are broken down into smaller size by the use of high
pressure homogenization, pearl milling and wet ball milling. Disadvantage of the top-down process
is the requirement of high energy for the reduction of particle size, chemical degradation by milling
and more possibility of the contamination by grinding media. On the other hand Bottom-up
processes are basically precipitation processes, where drug is dissolved in an organic solvent and
the precipitation of the drug particlesoccur by the addition of antisolvent in the presence of
stabilizer from the supersaturated solution of drug. Various adaptations which increase the
precipitation such as solvent- evaporation, reduction in temperature or by addition of antisolvent
(Verma et al., 2009; Sinha et al., 2013; Möschwitzer, 2013)Drug crystal size cannot be controlled in
this process which is the disadvantage of most currently applied bottom-up processes, therefore,
amorphous solid dispersion was prepared to overcome these disadvantages (Shekunov et al., 2006;
Kipp, 2004).The amorphous solid dispersion was prepared by novel bottom-up process, which is
developed by D.J. van Drooge etalbased upon freeze dryingusing combination of tertiary-butyl
alcohol (TBA) and water as solvent and anti-solvent (co-solvent) system (Van Drooge et al., 2004;
Waard et al., 2009; Waard et al., 2008).
Lovastatin (LOV), isolated from strains of Aspergillusterreus, belongs to the BCS class II drug,
exhibits poor oral bioavailability (< 5%) due to low water solubility and undergoes rapid
metabolism in the gut and liver (Chen et al., 2010). LOV is a prodrug rapidly hydrolyzed to the
corresponding β-hydroxyacid metabolite a competitive inhibitor of 3-hydroxy-3-methyl-glutaryl-
Co-enzyme A (HMG-CoA) reductase use for lowering of cholesterol in those with
hypercholesterolemia and so preventing cardiovascular disease. HMG-CoA reductase enzyme is
essential for the biosynthesis of cholesterol that catalyzed the early rate limiting step i.e. the
12
conversion of HMG-CoA to mevalonate. Lovastatin and its active metabolite have short elimination
half-lives (1-2hr.),which make frequent dosing necessary to maintain therapeutic blood levels for
longer treatment. A formulation with a high degree of oral absorption and extended delivery
potential would be highly desirable for Lovastatin (Ochoa et al., 2011; Suresh et al., 2007; Wang et
al., 1991; Chena et al., 2013).
In the present study SD of LOV with the mannitol hydrophilic carrier was prepared by bottom-up
process based upon freeze drying. The objective of the present work was to improve the solubility
of LOV by solid dispersion prepared by freeze drying employing mannitol as a hydrophilic carrier
and to incorporate solid dispersion into sustained-release tablet dosage form.
2. Materials and Methods

2.1 Materials
Lovastatin was obtained as a gift sample from Concord biotech Ltd. Ahmadabad (Gujarat) India.
Mannitol and t-butyl alcohol (TBA) were purchased from Fisher scientific and RFCL limited, India
respectively. HPMC K15, Lactose, Starch, Microcrystalline cellulose, Magnesium Stearate was
purchased from HIMEDIA® laboratories Pvt. Ltd. andEthyl cellulose ( Ethocel 20cps) was purchased
from LobaChemie Pvt. Ltd, Mumbai, Indiarespectively.All other chemicals and reagents were of
analytical grade and used as provided.
2.2 Methods
2.2.1. Saturation solubility studies

Saturation solubility studies were performed according to the method described by Hecqet al
(Hecq et al., 2005).Saturation solubility of Pure LOV and SD prepared by freeze drying containing
an equivalent amount of drug (5mg) were added to 25 ml stoppred conical flask containing 20 ml of
different media (distilled water, 0.1 N HCl, and Phosphate buffer pH 6.8). Samples were sonicated at
room temperature for 5 min and flasks were shaken for 24 hrs in orbital shaking incubator (Remi,
India) at 37 ± 2 C. After shaking to achieve equilibrium, 4 ml aliquots were withdrawn and passed
through Whatman filter paper no.41. The amount of drug dissolved was analyzed
spectrophotometrically (UV/Visible Spectrophotometer, U-2900, Hitachi, Japan) at 238 nm.
2.2.2. Preparation of the Solid dispersion

Solid dispersion of LOV was prepared by a bottom-up process, according to the method described
by de Waard et al (Waard et al., 2008). Accurately weighed quantity of LOV and Mannitol were
dissolved in t-butyl alcohol (TBA) & water (25mg/ml each) respectively, according to the design
given in Table1. After gentle heating up to 35-40 0C, the aqueous solution was mixed with a TBA
solution in 20 ml of pre-chilled glass injection vials. Immediately after mixing, uncontrolled freezing
of solution was done. Freeze drying was performed by using Programmable freeze Dryer
(Lyophilizer, Make M/s Labogen Aps, Denmark). The frozen solution was lyophilized at a pressure
of 0.005mBar for 42 hrs.
13
Table 1 Solubility of Lovastatin in solid dispersions

Batch Lovastatin Mannitol Ratio of water: TBA Solubility in water
Code (mg/mL) (mg/mL) (V/v) (mg/mL)
SD 1 100 125 4:5 0.0066
SD 2 100 150 4:6 0.0054
SD 3 100 100 4:4 0.0061
SD 4 175 125 7:5 0.0116
SD 5 175 112.5 7:4.5 0.0089
SD 6 175 137.5 7:5.5 0.0064
SD 7 250 112.5 10:4.5 0.0094
SD 8 250 125 10:5.5 0.0101
SD 9 250 100 10:4 0.0053
2.2.3. Preparation of Sustained-Release Matrix Tablet

Lovastatin sustained-release matrix tablets with a theoretical weight of 400 mg were prepared,
according to the proportions specified in Table 2by wet granulation methods. Tablets of different
batches containing 48 mg LOV solid dispersion powder (equivalent to 20 mg dose of LOV) were
prepared. Lyophilized powder, HPMC K15 and Ethocel 20cps, as polymeric matrix materials, alone
or in combination and other preparation excipients were passed through sieve “No.20”, separately.
Mixing of powders was carried out with multipurpose equipment (Orchid scientific, India). A 5%
starch paste was added to this mixture drop wise with continuous mixing. The wet mass was
passed through mesh sieve “No. 20” and it was dried at 50 0C in an oven for 1 hr. Then, the granules
were sized by passing through a “No. 30” mesh sieve screen and thoroughly mixed with 1% (w/w)
magnesium stearate. Finally, 400 mg of each blend was weighed and compressed using KBr press
(single punch compressor) with 13 mm flat, round, punch. The maximum compactionload was 4-5
kN.
Table 2 Composition of Sustained Release Matrix Tablets of Lovastatin

Formulation Lyophilized HPMC Ethocel Lactose Avicel Magnesium
Code Powder K15 M 20 cps 101pH Stearate
R1 48 75 25 100 151 1
R2 48 50 50 100 151 1
R3 48 25 75 100 151 1
R4 48 100 0 100 151 1
R5 48 0 100 100 151 1
All quantities from table are in mg.
2.3. Physical characterization of solid dispersion

Solid state characterization of pure LOV, Mannitol and optimized batch (7:5 ratio of LOV and
Mannitol) of solid dispersion was performed.
2.3.1. Differential scanning calorimetry (DSC)

Thermal behavior of the samples was determined by Differential Scanning calorimetry (DSC-60,
Shimadzu & 821, Mettler Toledo). The accurately weighed samples (5-10 mg) were sealed in an
14
aluminum pan. The samples were scanned at a temperature range of 30 °C to 400 °C at the rate of
10 °C/min under dry nitrogen atmosphere purge of 50mL/min.
2.3.2. X-ray diffraction (XRD)

X-ray diffraction analysis of samples was carried out to characterize the physical form i.e.
amorphous or crystallinenature of LOV in samples of optimized batch in an X-ray diffractometer
(D8 Advance, Bruker) with Cu Kα radiation (λ=1.54060A°).The scanning rate 10/min and
diffraction angle 2 was 10-80.
2.3.3. Field Emission Scanning electron microscope (FE-SEM)

The particle morphology of the samples was carried out using scanning electron microscopy (FE-
SEM, Type-II, Model-S-4800, Hitachi, Japan) .The surface morphology was analyzed at a working
distance of 8.7-8.8 mm and 1.0 kV accelerating voltage.
2.3.4. Particle size distribution

The particle size distribution was determined in water as a dispersion medium by laser diffraction
size analyzer using a Malvern Zetasizer (Model, ZS 200).
2.3.5. Tabletting
All formulations were compressed to 13 mm round and flat tablets having a weight of
approximately 400 mg. The maximum compaction load was 5 kN. All tablets were prepared by
direct compression method on a KBr press (model m-15), and the die was lubricated with
magnesiumstearate. Each 400 mg tablet contains a solid dispersion (equivalent to 20 mg LOV),
Mannitol, lactose, Avicel 101pH, and stearic acid.
2.4. Characterization of sustained-release tablets
2.4.1. Fourier transforms infrared spectroscopy (FTIR)

Drug polymer interactions were studied by using a FTIR spectrophotometer (Shimadzu, FTIR-
8400). FTIR analysis of the pure drug, polymer and solid dispersion of Lovastatin was carried out
by KBr pellet method. Sample (2 mg) was mixed with KBr and compressed into a disc in a manual
press. The spectrum was scanned from 4000 to 400 cm-1.
2.4.2. Characterization of granules

The granules were evaluated for Bulk density, Tapped density, Angle of repose, Carr’s indexand
Hausner’s Ratio.
2.4.2.1. Bulk density and Tapped density

Bulk density and tapped density were determined by cylinder method.
Bulk density = Weight of powder / Bulk volume (I)
Tapped Density = Weight of powder / Tapped volume (II)
2.4.2.2. Angle of repose

Angle of repose was determined by funnel method.
Tan θ =h/r (III)
15
2.4.2.3. Carr’s Index

Carr’s Index was determined by the following equation-
Carr’s Index (%) = [(TD-BD) x100]/TD (IV)
Where ‘TD’ and ‘BD’ is bulk density and tapped density.
2.4.2.4. Hausner’s Ratio

The Hausner’s ratio is a number that is correlated to the flow ability of a powder or granular
material.
Hausner’s Ratio = TD / BD (V)
2.4.3. Characterization of tablets
2.4.3.1. Tablet thickness

Thickness of the 10 randomly selected tablets was determined using vernier caliper (Aerospace,
India). Results are expressed as mean values ± SD.
2.4.3.2. Tablet hardness

The hardness of the tablets was measured using a Monsanto hardness tester. Ten randomly
selected tablets per batch were measured .Results are expressed as mean values ± SD.
2.4.3.3. Tablet weight variation

For the determination of weight variation of each batch, 10 tablets were randomly selected and
accurately weighed with an electronic balance (Shimadzu, Au (200). Results are expressed as mean
values ± SD.
2.4.3.4. Tablet friability

The friability of the tablets was determined using 10 randomly selected tablets from each batch and
placed in the drum of tablet friability test apparatus (Roche friabilator, Adinath industries, Mumbai)
at a speed of 100 rpm for 4 min. The tablets were weighed before and after the friability test, and
friability was determined as percent weight change.
2.4.3.5. Drug content uniformity

Five tablets were individually weighed and finely powdered by pestle in a mortar. Powder sample
equivalent to 20 mg of Lovastatin was accurately weighed and transferred to a 100 mL volumetric
flask. Initially 50 mL of methanol was added to the volumetric flask and allowed to stand for 10 min
with intermittent sonication to ensure complete solubility of the drug. Then the volume was made
up (100 mL)with methanol and filtered through a whatman filter paper (No.41).Lovastatin content
was analyzed by double beam ultraviolet spectrophotometer at a wavelength of 238 nm.
2.4.3.6. In-Vitro drug release studies

Drug release studies of the prepared Lovastatin tablets were performed, in a Tablet Dissolution
Test Apparatus, Type-II (Paddle method, Electrolab, TDT 06) at 37±0.5 0C and at paddle speed of 50
rpm. The release studies were carried out in a 900 mL dissolution medium of pH 1.2 for the first
2hrs, and continued in phosphate buffer pH 6.8 up to 24 hrs. Change in pH (from pH 1.2 to pH 6.8)
was made by an addition of 0.2M tribasic sodium phosphate. All Dissolution media was contained
0.2% Sodium lauryl sulphate (SLS).
16
5 mL sample was withdrawn from the dissolution apparatus at different time intervals and filtered
through membrane filter .The drug content was determined at 238 nm by Double beam ultraviolet
spectrophotometer. The withdrawn sample was replenished with 5mL of fresh media.
2.4.3.7. Kinetic analysis of drug release profiles

To study the drug release mechanism from sustained release tablets the release data were fitted to
zero-order kinetics, first-order kinetics (Costa and Lobo, 2001),Higuchi model and Korsmeyer-
Peppaskinetics models (Sharma et al., 2011). The kinetic model with the highest value of the
coefficient of correlation (r2) was considered to be a best fit model for describing the release of LOV
from the sustained-release tablets.
3. Results and discussions

3.1. Saturation solubility
The saturated solubility of pure Lovastatin and SD of Lovastatin in distilled water, 0.1 N HCl and
phosphate buffer (pH = 6.8) are shown in Fig 1.A saturation solubility study revealed that LOV
shows maximum solubility in phosphate buffer (pH 6.8) and was found to be 0.031mg/ml and in
solid dispersion was 0.179 mg/ml. Therefore, phosphate buffer (pH 6.8) was chosen for dissolution
medium. The saturation solubility ofLOV in SD was enhanced 5-6 fold than pure drug.
Fig. 1. Solubility of Lovastatin in solid dispersion and pure Lovastatin using different media
3.2. DSC
DSC thermogram of pure LOV and an optimized batch of SDare shown in Fig 2.Thermogram of pure
LOV showed a sharp endothermic peak at 173.5 C which corresponds to melting point of the drug,
which is same as reported in literature. A result of DSC analysis confirms the identity and purity of
the drug. There was a reduction in endothermic peak in solid dispersion as compared to pure LOV,
suggesting that the interactionbetween thedrug and hydrophilic carrier occurs and due to changes
in physical form crystalline to amorphous state (Maulvi et al., 2011).
17
Fig. 2. DSC thermogram of [A] pure Lovastatin and [B] Lovastatin solid dispersion
3.3. X-RD
The X-RD patterns of pure LOV, mannitol and solid dispersion are shown in Fig 3. The diffraction
spectra of pure LOV showed sharp and intense peaks of crystallinity. On the other hand X-RD
pattern of solid dispersion prepared by freeze drying showed reduction in number and intensity of
the peaks in compared to the pure LOV indicates that the decrease in crystallinity or slightly
amorphous nature of the drug. Data given from X-RD analysis shows that pure drug is 89.4%
crystalline and in SD crystallinity decreases to 60.2%. Thus less intense peak in SD as compared to
pure drug indicates amorphous nature results in higher solubility and dissolution rate as compared
to pure drug (Newman et al., 2012).
Fig. 3. XRD spectra of pure Lovastatin, Mannitol and Lovastatin Solid dispersion
18
3.4. FE-SEM
The field emission scanning electron micrographs (FESEM) of the solid dispersion prepared by
freeze drying are shown in Fig 4. SD had irregular and rod shape structure with rough surface. As
well as particle size decreases, surface area increases suggesting that mannitol a hydrophilic carrier
was attached to the surface of drug may be responsible for enhancement of solubility and
dissolution rate of SD particles (Choudhary et al., 2012).
Fig. 4. FE-SEM photographs of Lovastatin solid dispersion
3.5. Particle size distribution

Particle size distribution of pure drug and LOV in solid dispersion was shown in Fig 5.Mean size (d.
nm) of pure drug andSD formulation were found to be 1.718 µm (Fig.5A) and 712.5 nm (Fig.5B),
respectively. Results of particle size distribution showed reduction in particle size, which is
responsible for solubility enhancement due to increased surface area.
19
Fig. 5. Average size (d. nm) of [A] pure Lovastatin and [B] Lovastatin solid dispersion
3.5. Fourier transform infrared spectroscopy (FTIR)

The FTIR spectra of pure LOV, mannitol, polymer, solid dispersion and tablet blend of optimized
formulation shown in Figure 6. Spectrum of pure drug showed characteristic peaks at 3541.42 cm-1
corresponding to the (alcohol O-H stretching),2962 and 1717.67cm-1 (lactose, C=Ocarbonyl
stretching), 1454.38 cm-1 (methyl asymmetric bending),1261.49 cm-1 (lactone, ester C-O-C
asymmetric bend), 1066.67cm-1 (C-C symmetric bend), 1220 cm-1 (C-O,alcoholicbending), 1381 cm-
1 (C-H, Methylene asymmetric stretching).
In LOV solid dispersion O-H stretching shifted towards lower frequency 3538.53 cm-1 and carbonyl
(C=O) stretching towards 1702.24 cm-1, due to the interaction between the hydroxyl group (-OH)
mannitol and carbonyl (C=O) group of pure LOV (Maulvi et al., 2011). From the result, it is found
that there are no major shifts in the positions of bands of pure drug in comparison to the
formulations of drug which suggested that there is no interaction between the drugs, polymer and
excipients used in the preparation of SD and sustained release tablets.
20
Fig. 6. FTIR spectra of [A] pure Lovastatin, Mannitol and [B] Lovastatin Solid dispersion tablet
formulation (R2)
3.6. Characterization of granules and tablets

The granules of the tablets were prepared according to the proportions given inTable 3and
characterized for their flow properties as shown in Table 3. The bulk density was found to be in the
range of 0.431±0.13 to 0.479±0.13 g/mL and tapped bulk density in the range of0.504 ±0.28 to
0.548 ± 0.37 g/mL.Angle of repose of all the formulations ranging from 22.10 ±0.52 to 25.40 ± 0.84
() indicating good flow property. Carr’s index ranging from 11.83 ± 0.41 to 15.28 ± 0.23 (%) and
Hausner ratio ranged from 1.13 ± 0.11 to 1.19 ± 0.05 for granules of different formulation. These
values revealed that prepared granules of all the formulations show good flow properties.
Table 3 Evaluation of granules

Form. AR LBD TBD CI HR
Code () (g/mL) (g/mL) (%)
R1 25.40 ± 0.84 0.438 ± 0.09 0.517 ± 0.32 15.28 ± 0.23 1.18 ± 0.08
R2 24.86 ± 0.67 0.431 ± 0.13 0.504 ± 0.28 14.48 ± 0.19 1.16 ± 0.04
R3 22.90 ± 0.56 0.442 ± 0.32 0.528 ± 0.42 14.04 ± 0.34 1.19 ± 0.05
R4 22.10 ± 0.52 0.462 ± 0.16 0.524 ± 0.26 11.83 ± 0.41 1.13 ± 0.11
R5 24.38 ± 0.76 0.479 ± 0.13 0.548 ± 0.37 12.59 ± 0.28 1.14 ± 0.16
All values are expressed as mean ± SD (n3); Form. Code= Formulation code
AR = Angle of repose; LBD = Loose bulk density; TBD = Tapped bulk density; C I = Carr’s index; HR =
Hausner’s ratio
The tablets of different formulations were subjected to various evaluationtests and are summarized
in Table 4.The thickness and hardness of all tablet formulations ranged from 3.84 ± 0.05 to 4.08 ±
0.11 mm and 5.4 ± 0.26 to 6.3 ± 0.19 kg/cm2 respectively. All the tablet formulations showed
acceptable physicochemical properties and met thePharmacopoeial requirement of hardness,
thickness, weight variation, friability and drug content. The percentage friability of all the
formulations was found to be less than 1% which is in limit and weight variation ranges from
396.23 ± 1.32 to 401.14 ± 1.43 mg. Results of drug content uniformity was found to be good among
different formulations of the tablets and percentage of drug content were found in between 97.89 ±
0.79 to 100.21 ± 0.87 (%).
21
Table 4 Evaluation of Lovastatin Tablets

Form. Thickness* Hardness Friability* Weight variation* Drug content**
Code (mm) (kg/cm2) (%) (mg) (%)
R1 3.84 ± 0.05 5.9 ± 0.16 0.42± 0.08 397.21 ± 1.52 99.69 ± 0.92
R2 3.87 ± 0.10 6.1 ± 0.21 0.36 ± 0.05 401.14 ± 1.43 99.32 ± 1.07
R3 4.02 ± 0.08 5.8 ± 0.11 0.42 ± 0.13 396.23 ± 1.32 98.39 ± 1.18
R4 3.91 ± 0.05 5.4 ± 0.26 0.47 ± 0.05 400.36 ± 1.76 100.21 ± 0.87
R5 4.08 ± 0.11 6.3 ± 0.19 0.31 ± 0.10 396.45 ± 1.48 97.89 ± 0.79
*All values are expressed as mean ± SD (n10); **All values are expressed as mean ± SD (n5)
3.7.In vitrodrug release studies
In vitro drugrelease studies were performed to determine the percentage of drug release from the
formulated sustained release matrix tablets in gastric fluid and intestinal fluid. The drug release
was performed for the first two hours in pH 1.2and in pH 6.8 for next 22 hrs. The release patterns of
LOV from different batches of formulating matrix tablet areshown in Fig 7. The drug release from
the matrix tablet using HPMC K15 and Ethocel 20 cps was found to be in the range of 9.45 to 32.14
in % first 2 hrs at pH 1.2 and 99.47 % up to 22hrs in intestinal fluid (pH 6.8) indicating that drug
released from the matrix tablets depends upon the composition of the release retarding polymer
which varies in one formula to another. When compared the formulation R1 to R5, sustained release
up to 24 hrswas observed in the formulation R2. The release of drug in the formulation R2 was in the
optimized condition as required, when the polymer matrix used in the ratio of 1:1. This may be due
to the high viscosity of HPMC K15 (Hydrophilic polymer), which on contact with dissolution
medium, surface of tablet become wet and swell to form viscous gel layers. As the concentration of
HPMC K15 increases, thickness of gel layer increases while the diffusion coefficient of drug
decreases (Tadros, 2010). Further, incorporation of varying concentration of Ethocel 20cps in
sustained released tabletsresulted in a reduced diffusion of drug from the matrix. Hence,
mechanism of drug released from matrix tablets involve the penetration of water into the matrix by
hydration and diffusion of the drug dissolved in the matrix due to swelling of the polymer.
Fig. 7. In-Vitro drug release profile of Lovastatin solid dispersion sustained-release tablet of all the
formulations
22
In-vitro drug release of Lovastatin(pure) from the tablet formulation without polymer (control)that
is physical mixture was found to be61.45 % in 1 hour.In-vitro drug release behaviour of Lovastatin
solid dispersion tablet prepared by direct compression method was compared to the tablet
prepared with pure drug(control).It is observed that solid dispersion tablet formulation showed
more drug release 87.98 % within 1 hour than the corresponding tabletsshown in Figure
8.Enhancement in the drug release or dissolution rate of Lovastatin from solid dispersion tablet can
be due to the reduction in particle size,reduced crystalline nature, adsorption of drug on
hydrophilic carrier and interfacial tension decreases between the drug and dissolution medium due
to hydrophobic nature of drug.
Fig. 8. Dissolution rate profile of Lovastatin tablets composed of physical mixture and Lovastatin
solid dispersion (7:5 ratio of TBA/Water)
To study the release behavior of Lovastatin from matrix tablets, the release data were fitted to the
various kinetic models such aszero-order, first-order, Higuchiand Korsmeyer-Peppas kinetics
models. In this present study in-vitro drug release profile of optimised formulation (R2) followed
first-order kinetics and plot showed highest regression coefficient (r20.997).The slope (n) value
obtained from Korsmeyer-Peppas model was found to be more than 0.89 indicating super case-II
transport, i.e. drug release by both diffusionand relaxation of the polymer chain, Lovastatin
exhibited super case-II transport as dominated mechanism for optimized formulation (Shoaib et al.,
2006; Siepmann and Peppas, 2001).
4. Conclusion
In the present study we have used a bottom-up process based upon freeze drying to prepare
Lovastatin solid dispersion to increase solubility and dissolution rate. The FTIR, DSC and XRD
studies showed partial interaction between the Lovastatin and hydrophilic carrier. Result obtained
from XRD showed that decrease in crystalline nature of drug in solid dispersion. Increase in
solubility and dissolution rate of optimized formulation of solid dispersion (7:5 ratio of TBA/water)
occur due to the conversion of crystalline nature of drug to amorphous nature and decrease in
23
particle size of drug. In the present work sustained release tablets were prepared by using HPMC
K15 and Ethocel 20 cps as polymer matrix. Preparation of matrix tablets by wet-granulation
technique was found to be more effective in sustaining the release of drug. In-vitro drug release
study of Lovastatin revealed that drug release rate was dependent on polymer concentration.
R2formulation was concluded as optimal formulation in term of drug release profile showed the
sustained drug release up to 24 hrs. The kinetic studies revealed that optimized formulation
followed first-order kinetics and mechanism involving a combination of both diffusion and
relaxation of polymer chain.The matrix tablets of Lovastatin release the drug over a period of 24 hrs
from optimized formulation R2 employingHPMC K15 and Ethocel ratio 1:1. Hence, itcan be
concluded from the study that the combination of hydrophilic and hydrophobic polymers could be
successfully employed for the formulation of sustained-release matrix tablet.
Acknowledgements
The authors are thankful to University Grant Commission (UGC),New Delhi, for providing financial
support. The authors also like to thank Concord Biotech Ltd., Ahmadabad, Gujarat (India) for
providing the gift sample of Lovastatin.
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Preparation of Freeze-dried Solid Dispersion Powder using Mannitol to Enhance

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Umakant Verma Jitendra Naik

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Preparation of Freeze-dried Solid Dispersion Powder

UmakantVerma1, J. B. Naik1*and V.J. Mokale1

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2. Materials and Methods

2.2.1. Saturation solubility studies

2.2.2. Preparation of the Solid dispersion

Table 1 Solubility of Lovastatin in solid dispersions

2.2.3. Preparation of Sustained-Release Matrix Tablet

Table 2 Composition of Sustained Release Matrix Tablets of Lovastatin

2.3. Physical characterization of solid dispersion

2.3.1. Differential scanning calorimetry (DSC)

2.3.2. X-ray diffraction (XRD)

2.3.3. Field Emission Scanning electron microscope (FE-SEM)

2.3.4. Particle size distribution

2.4. Characterization of sustained-release tablets

2.4.1. Fourier transforms infrared spectroscopy (FTIR)

2.4.2. Characterization of granules

2.4.2.1. Bulk density and Tapped density

2.4.2.2. Angle of repose

2.4.2.3. Carr’s Index

2.4.2.4. Hausner’s Ratio

2.4.3. Characterization of tablets

2.4.3.1. Tablet thickness

2.4.3.2. Tablet hardness

2.4.3.3. Tablet weight variation

2.4.3.4. Tablet friability

2.4.3.5. Drug content uniformity

2.4.3.6. In-Vitro drug release studies

2.4.3.7. Kinetic analysis of drug release profiles

3. Results and discussions

Fig. 4. FE-SEM photographs of Lovastatin solid dispersion

3.5. Particle size distribution

3.5. Fourier transform infrared spectroscopy (FTIR)

3.6. Characterization of granules and tablets

Table 3 Evaluation of granules

Table 4 Evaluation of Lovastatin Tablets

3.7.In vitrodrug release studies

tableting properties of cefuroxime axetil by melt-granulated dispersion and surface adsorption.Acta

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