Post on 04-Jul-2020
22.. LLiitteerraattuurree RReevviieeww
CChhaappeerr 22 hhaass bbeeeenn ppuubblliisshheedd iinn tthhee ffoolllloowwiinngg jjoouurrnnaallss::
�� SSaauuddii PPhhaarrmmaacceeuuttiiccaall JJoouurrnnaall ((EEllsseevviieerr ppuubblliiccaattiioonn))
�� RReecceenntt PPaatteennttss oonn DDrruugg DDeelliivveerryy aanndd FFoorrmmuullaattiioonn ((BBeenntthhaamm sscciieennccee ppuubblliiccaattiioonn))
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 14
2.1 Review of spray drying technology
2.1.1 Introduction
In recent times, many new chemical entities (NCEs) have been synthesized on the
basis of structure of their target receptors using combinatorial chemistry, which results in
the invention of very large molecules with greater degree of hydrophobicity. Their poor
aqueous solubility may cause poor solubilization in gastrointestinal tract with low and
unpredictable bioavailability [1]. It is frequently documented that almost 40% of NCEs
discovered by the pharmaceutical researchers are poorly soluble or lipophilic in nature
[2]. The solubility performance of drugs remain one of the most challenging qualities in
formulation development and it results into challenge in targeted delivery of poorly water
soluble drugs [3]. Solid dispersion is one of methods which involves dispersion of one or
more active ingredients in an inert carrier or matrix in solid state prepared by melting,
dissolution in solvent or solvent evaporation method [4]. Solid dispersion based spray
drying technology is widely applied in pharmaceutical industry because it is simple,
economic and advantageous [4]. Commercial scale solid dispersion can be produced
mainly by 3 processes: hot melt extrusion, spray drying and freeze drying [5]. By
increasing the bioavailability, less quantity of drug is required to produce the same
therapeutic effect and it also reduces the excessive dose administration in patient’s body
which results into increased patient compliance as well as reduced cost of final
formulation [6,7]. Current research work covers an overview of spray drying technology,
critical process parameters (CPPs) and their effect in final product quality, effect of
various additives in spray drying, screening methodology for selection of suitable carrier
polymer, characterization of amorphous solid dispersion using various thermal analytical
methods, scale-up in spray drying and in vitro in vivo correlation (IVIVC) of spray dried
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 15
formulation. Quality by design (QbD) is also an important aspect in optimization of the
spray drying process parameters to assure the desirable reproducibility and quality of final
product; therefore, it has also been covered under this review.
2.1.2 Need of solubility enhancement in pharmaceutical development
The solubility of a drug plays a vital role in drug disposition because the main
pathway for drug absorption is a function of permeability and solubility. Higher solubility
results in better absorption in the gastrointestinal tract, reduced dosage-level requirements
and better therapeutic effects. As shown in Figure 2.1, absorption of a BCS class II drug
can be significantly improved by optimization the formulation in such a way that it
maintains class II drugs in a solubilized condition at the absorption site and due to that it
gives a similar absorption profile like that of a class I molecules. For BCS class III and IV
molecules, the permeability and absorption can be improved by means of chemical
modification during the drug synthesis [8]
Figure 2.1 Biopharmaceutics (BCS) classification [modified from Ref. 8]
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 16
2.1.3 Various methods to overcome solubility issue
As shown in Table 2.1, various physical and chemical methods can be used to
improve the solubility of poorly water soluble drugs. Particle size reduction is one of the
physical methods to enhance solubility, but sometime decreasing the particle size may
cause the agglomeration, which may retard the solubility and bioavailability during
storage of final product. Presenting the compound as a molecular dispersion combines the
benefits of a local increase in the solubility as well as stability of amorphous form of drug
[9]. Selection of right carrier polymer is also vital to improve solubility, so one
mathematical tool for selection of the right excipient for solid dispersion technology has
also been covered in current review.
Table 2.1 Various technologies for solubility enhancement [3, 5, 9]
Physical methods Chemical modification
Particle size reduction (micronization or
nanosuspensions)
Salt formation
Polymorphism Prodrug approach
Change in crystal habit
Complexation/solubilization (use of surfactantsor use of
cyclodextrines)
Drug dispersion in carriers (solid dispersions)
2.1.4 Solid dispersion technology
Solid dispersion is defined as the dispersion of one or more active ingredients in
an inert excipient or matrix (carrier), where the active ingredients could exist in finely
crystalline, solubilized or amorphous state [10, 11]. Solid dispersion is consisting of 2 or
more than 2 components, generally a carrier polymer and drug along with stabilizing
agent (and/or surfactant or other additives) and that’s why it is also known as ternary
solid dispersion. Ternary solid dispersion is also currently increasing interest in order to
stabilize the amorphous form during storage. The most important role of the added
polymer in solid dispersion is to reduce the molecular mobility of the drug to avoid the
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 17
phase separation and re-crystallization of drug storage. The increase in solubility of the
drug in solid dispersion is mainly because drug remains in amorphous form which is
associated with a higher energy state as compared to crystalline counterpart and due to
that it required very less external energy to dissolve [12]. Additionally, formation of small
particle size with better porosity, wettability and surface area are the main reasons for the
improvement in bioavailability [13].
There are basically 2 types of solid dispersion systems: crystalline and amorphous
solid dispersions [14, 15]. Former system contains the crystalline drug dispersed within a
crystalline or semi-crystalline carrier. Later system contains a carrier which is amorphous
rather than crystalline, and it can be additionally classified into solid crystalline
suspension, solid glassy suspension, and solid glassy solution [16]. As shown in Figure
2.2, solid glassy solutions containing drug and carrier are homogeneous and molecularly
dispersed with each other in single homogeneous phase and in differential scanning
calorimetry (DSC), it shows single glass transition temperature (Tg) peak. Solid glassy
solution is the best system to achieve solubility enhancement with good thermal and
physical stability. 2 phase blends also known as solid glassy suspensions contain drug in
partially miscible state with the carrier and are more prone to undergo phase separation
during storage. Solid crystalline suspension contains polymer in amorphous phase while
drug in crystalline phase and in DSC it shows one Tg peak for polymer and one melting
peak for drug which indicates no miscibility between drug and the polymer. Amorphous
solid dispersions are commercially manufactured either via spray drying of an organic
solution or by melt extrusion of a powder blend [16]. To accomplish the substantial
stability of solid dispersion, pharmaceutically suitable carriers like polymers, surfactants
and stabilizers are added into the formulation, usually at high concentrations to reduce the
molecular mobility and re-crystallization of drug [16]. By looking current development
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 18
scenario, there is a significant interest in developing an amorphous solid dispersion to
solve the solubility and bioavailability issue of BCS class II and IV molecules [17-21].
Figure 2.2 classification of solid dispersion
2.1.5 Screening of polymer in solid dispersion technology
With the aim to accomplish the desired solubility and stability of amorphous form
of drugs, selection of right polymer(s) or carrier(s) is required in the initial stage of
formulation development. Excipients screening or selection would be time-consuming
and requires an extra labor with consumption of a large amount of drug. In the early
phase of lead optimization and candidate selection, large numbers of hydrophobic
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 19
compounds are synthesized in very small quantities and, therefore well efficient polymer
screening method is required which consumes minimum amount of drug [22-23].
Dai and co-workers have developed experimentation approaches to rapidly
identify a solubility-enhancing polymer that improved the bioavailability of a poorly
water-soluble compound. In the experiments, the lead compound and a panel of
excipients were dissolved in common organic solvent like n-propanol and distributed into
the wells of a 96-well micro titer plate by a TECAN (innovative liquid handling
workstation) robot. After solvent evaporation, the dried formulations were further diluted
with an aqueous buffer and incubated for 24 hr and the solubilization capacity of the
excipients was analyzed by HPLC [24]. Moreover, the optimized formulation can be
scaled up and developed using various methods like hot melt extrusion or spray drying to
compare the actual solubility and screening experimental solubility [25]. Barillaro and
coworkers have also evaluated total 108 experiments containing 7 different polymers and
5 different surfactants to study the dissolution property of phenytoin [26]. Similarly,
Mansky and team have also developed in house and well efficient screening method to
identify lipid and semisolid formulations for low soluble compounds [27]. The limitation
of all above mentioned method is that it requires consumption of drug and requires extra
labor for analytical study to identify suitable polymer. So, various pharmaceutical
companies, service provider and excipient manufacturer companies are working on
various novel approaches for improving solubility of poorly soluble drugs using solid
dispersion technology [28].
Other approach like solubility-parameter estimation and molecular-interaction
considerations are important tools in estimating first formulations in solid-dispersion
product without consumption of API [28]. Recently, an excipient manufacturer company
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 20
“Evonik Industries AG, Germany” has developed one mathematic tool named as melt
extrusion modeling and formulation information system (MEMFIS) to ensure the best
possible start in a melt extrusion or solid dispersion based project by giving estimations
for both the extrusion process as well as initial formulation. MEMFIS helps in selecting
initial formulations without API consumption, using mathematical models and algorithms
based on solubility parameter theories. High-throughput screening is accomplished based
upon molecular structure, intra- and inter-molecular bonding, and their impact on
solubility parameters [28]. MEMFIS kinds of tool are very effective for poorly soluble
NCE molecules, as initial quantity of NCE during drug discovery clinical stage are very
less and consumption of drug for every trials is also quite costly. So, MEMFIS tool gives
idea about the selection of right polymer to produce a stable solid glassy solution as well
as the miscibility of drug into suitable polymer.
2.1.6 Background of spray drying technology
Spray drying technology can be defined as a unit operation in which a liquid
stream (solution, suspension or emulsion) is constantly divided into very fine droplet (by
a process known as atomization) into a glass compartment where they come in contact
with hot gas and get dried into fine particles, which are further separated from the drying
gas using a cyclone or a bag-filter [29]. Spray driers can operate in open cycle mode for
aqueous based or in closed-loop mode for organic based system. Spray drying is a
moderate drying technique (where gentle temperatures and little exposure times are used
as compared to other solid dispersion technology like melt extrusion) that yields powder
with reasonable particle size [30-31]. Moreover, the fast drying process within few
seconds or milliseconds is also important to prevent phase separation between the drug
and polymer components [12].
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 21
2.1.7 Advantages of spray drying technology over other solid dispersion methods
Spray drying technology is one of the most interesting technologies in the
pharmaceutical and food engineering field because it shows an outstanding potential to
manipulate the powder characteristics like particle size, morphology, density and level of
residual solvents, etc., due to that it is mainly useful for pulmonary drug delivery [32-34].
Moreover, in spray drying process, presence of carrier polymer may cause polymorphic
change in drug substances by transforming their low-energy crystalline form into high
energy amorphous form which provides the greatest advantage in terms of solubility of
drugs. However, because amorphous particles have a tendency to be metastable, the
amorphous state must be stabilized [35]. The main advantages of spray drying over melt
extrusion method are related to trouble-free processing of thermo labile compounds, the
flexibility in terms of formulation selection (since a suitable solvent system can help in
solubilization of most drugs with most polymers and other additives) and the facility to
control the final powder characteristics in terms of particle size distribution, flow
property, porosity, etc [12].
Alternative methods for the manufacturing of microparticles are co-acervation
based emulsion solvent evaporation which experiences various deficiencies such as
solvent residue remains in the finished product and difficulty in preparing small size
microspheres at higher scale and due to that spray drying becomes most user friendly
technology to prepare microparticles for solubility enhancement [34]. Moreover, in case
of thermo labile drugs, the same instrument can be operated at a lower temperature which
is called as spray congealing or spray freezing process [36-37]. Additional advantages
which spray drying process can offers are like bitter taste masking of drug [38], improved
drug stability and enhanced compressibility [39].
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 22
2.1.8 Critical process and formulation parameters in spray drying technology
Table 2.2, Figures 2.3 and 2.4 shows effect of critical process and formulation
parameters like spray rate, outlet temperature, solid concentration, atomization rate, etc.,
on the product characteristics of spray drying technology. These parameters in details
have been discussed below:
Table 2.2 Critical process parameters (CPP) and their influence in spray drying process
[modified from ref. 40]
CPP Significance in spray drying process
High
aspirator
rate
1. Due to more drying energy the outlet gas temperature may increase
2. Residual moisture in the final product may decrease
3. Offers more and uniform separation of particles in the cyclone
High solid
content or
high
viscosity
1. Due to more solid in a drop may increases the particle size
2. Produces bigger particles, which are easier to separate and increase yield
3. Decrease the moisture level in final product
High drying
gas
humidity
1. Gives moist particles which may adhere into the glassware and decreases
the process yield.
2. Might increase the humidity in final product
High feed
rate 1. Decrease the outlet temperature
2. Increase the droplet size and increase particle size
3. Increase the moisture level in the final product
High spray
gas flow 1. Decrease the outlet temperature
2. Produces smaller droplets and parallel particle size decreases.
High inlet
temperature 1. It increase the outlet temperature proportionally
2. Increase the yield and gives less sticky product
Organic
solvent 1. Use of organic solvent generates smaller particles due to lower surface
tension
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 23
Figure 2.3 Critical process and formulation variables in spray drying technology
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 24
Figure 2.4 Effect of process parameters in product characteristics [modified from 40]
2.1.8.1 Selection of solvent(s) and feed rate for spray drying technology
In order to make uniform and stable solid dispersions, the choice of solvent should
be selected very carefully for solvent based spray dryer because spray dryers are
generally sized based on their evaporative capability for a particular solvent. In general,
lower boiling solvents are very easy to evaporate and it results in higher solid production
yield [29]. Drug dissolution rates can be greatly influenced by drug concentration in the
feed solution, the choice of polymer, choice of surfactant and the ratio of
polymer/surfactant/drug [41]. Feed solution can be a reactive system and must be
evaluated in terms of impurity levels over a number of days due to possible chemical
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 25
reaction of drug with solvents and additives [42-43]. Solvents selection should be carried
out on the basis of following criteria like: boiling point, solubility of drug and polymer
and toxicity of solvent on the basis of ICH classification (like class III solvents are more
selected as compared to class I solvent due to less toxicity potential) [44-45]. Tables 2.3
and 2.4 highlights the possible carriers as well as commonly used solvents in spray drying
technology [44-48].
Table 2.3 List of carriers used for solid dispersion technology [12, 46-47]
Type of carrier Examples
Enteric polymer Poly(meth)acrylates (EUDRAGIT®
L 30 D-55 EUDRAGIT® L 100,
EUDRAGIT® S 100), hydroxypropyl methyl cellulose phthalate
(HPMCP), cellulose acetyate phthalate (CAP)
Hydrophilic
polymers
starch, sodium carboxymethyl cellulose, sodium alginate, polyethylene
glycol (PEG), polyvinyl pyrollidone (PVP), hydroxy propyl methyl
cellulose (HPMC), polyvinyl alcohol (PVA), β- cyclodextrin, mannitol,
chitosan, carrageenan
Surfactant polyethylene - polypropylene glycol, lecithin, bile salt, Lauroyl
polyoxyl-32 glycerides
Amphiphilic
polymers
polyethylene oxides (PEO,PEO/polypropylene glycol (PPG)
copolymers, PEG-modified starches, vinyl acetate/vinylpyrrolidone
random copolymers, polyacrylic acid and polyacrylates
Table 2.4 List of commonly used solvent in spray drying technology [44-45, 48]
List of solvents Boiling
point
(°C)
Dielectric
constant
Solubility in
water (g/100 g)
Density
(g/mL)
ICH Limit
(ppm)
Acetone 56.2 20.7 Miscible 1.049 class 3
Chloroform 61.7 4.81 0.795 1.498 60
Methanol 64.6 32.6 Miscible 0.791 3000
Methylene chloride 39.8 9.08 1.32 1.326 600
Ethanol 78.5 24.6 Miscible class 3
Dimethyl formamide 153 36.7 Miscible 0.944 880
Dimethyl sulfoxide
(DMSO)
189 47 25.3 1.092 class 3
Glycerin 290 42.5 Miscible 1.261 -
Ethyl acetate 77 6 8.7 0.895 class 3
Water 100 78.54 --- 0.998 -
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 26
Dielectric constant of solvent is also one of the important criteria for suitable
solvent selection in spray drying process because solubility of solute into solvent is
dependent on the dielectric constant of the medium. In simple terms, the energy required
to separate 2 oppositely charged bodies is inversely proportional to the dielectric constant
of the medium [49]. The addition of a co-solvent can increase the solubility of
hydrophobic molecules by reducing the dielectric constant of the solvent. Moreover,
water is a good solvent for polar molecules due to its high dielectric constant [49].
Jouyban and team had developed a simple computational method for calculating
dielectric constants of solvent mixtures based on Redlich-Kister extension. They found
that the model can be applied to the experimental dielectric constant of binary and ternary
solvent mixtures at fixed and/or various temperatures and it showed accurate results [50].
Moreover, changes in dielectric constant of the medium have a dominant effect on the
solubility of the ionizable drug mainly as higher dielectric constant can cause more
ionization of the drug and results in more solubilization [51].
In one of the research work, Al-obaidi and co-workers [52] have evaluated 2
different solvents combination for griseofulvin-PVP based spray drying technology. They
observed that solid dispersion prepared from acetone/ methanol (150/150) showed smaller
size particles as compared to acetone/water (185/85) solvent mixture. The viscosity of the
spray drying solution was lower for acetone-methanol (0.554 cP) than for acetone-water
(1.39 cP) and from that it would be anticipated that a dispersion resulting from the less
viscous solution that had a quicker rate of evaporation and gives small particle size.
Likewise, Harjunen and coworkers [55] have studied the effect of ethanol to water ratio in
feed solution and they found that lactose spray dried from pure ethanol was 100%
crystalline while lactose spray dried from pure water was 100% amorphous.
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 27
Esposito and co-workers [53] have observed that low feed rate gives a better result
in terms of morphology of prednisolone microparticles like moisture level, small particle
size and good flow property. Rattes and co-workers [54] have also found that slower
dissolution is obtained at higher feed rate and is partly due to the increase in the diameter
of the atomized drops at high feed flow rate which generates a bigger particle with lower
total surface area. So, physicochemical characteristics of spray dried powder are
significantly affected on the basis of selection of solvent, viscosity of feed solution,
concentration of solid in feed solution, feed rate, and to some extent by solution surface
tension.
2.1.8.2 Role of feed atomization on spray dried product characteristics
The aim of atomizer is to break down bulk liquid feed concentrate into fine
droplets in order to provide a very large surface, to facilitate solvent evaporation and
particle separations. Atomizer is appropriately fitted in the drying assembly along with
feed inlet to allow uniform mixing between feed solutions and drying gas [35]. The most
common atomizers used in pharmaceutical industry are 2-fluid nozzles (pneumatic
atomization), pressure nozzles (hydraulic atomization), rotary atomizers (rotating wheel
atomization) and ultrasonic atomizer [56-58]. The choice of atomizer depends upon the
properties of the feed and the dried product specification.
Current research scenario are much more focused towards the use of four fluid
spray nozzle in spray drying process to overcome the necessity of using common solvents
for 2 drugs. In one of the study, Mizoe and co-workers [59] have used 4-fluid spray
nozzle containing spray drier for preparing drug-containing microparticles of poorly
water-soluble drugs ethenzamide (EZ) and flurbiprofen (FP). They found that the 4-fluid
nozzle atomizer can overcome the problems of using a common solvent for 2 drugs as it
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 28
has 2 liquid and 2 gas passages, which allows drug and carrier to be dissolved in separate
solvents. Similarly, Chen and co-workers have prepared amorphous solid dispersion by
separately passing drug and polymer solutions all the way through four-fluid nozzle and
observed better performance in terms of effective distribution of particles in lungs with
enhanced absorption characteristics as compared to the microparticles prepared from a
single solution [60].
The particle size distribution obtained after traditional spray drying process is not
well controlled. So, in order to control the particle size and morphology electro hydro-
dynamic or electro-spraying (EHD) atomization is generally used in spray drying process
[61]. In EHD based atomization method, feed solution is first pumped through a nozzle
and the nozzle is applied with a high potential difference. The electrical field formed
causes the jet emitted from the nozzle to disintegrate into mono dispersed droplets in the
micrometer range [62]. Recently, Kuang and co-workers have studied about changing the
voltage applied to the electrodes on the particle size. They observed that particles
fabricated at a much lower voltage were of smaller diameter than particles fabricated at
higher voltage [62]. EHD is also used to produce fine particles of a complex structure
which are hard to obtain by other means [63]. So, electro spraying process has a unique
advantage to produce a narrow size distribution under the influence of electrical forces
which makes it more suitable for many pharmaceutical applications [64].
2.1.8.3 Effect of inlet/outlet temperatures on final product characteristics
Outlet air temperature is one of the most critical parameter which exclusively
affects the product morphology like particle size, surface roughness, density, stickiness of
particles, residual solvent or moisture levels, product yield, etc. After performing spray
drying process, secondary drying of powder is generally required to remove the excess
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 29
residual solvent. Because, presence of solvents may plasticize the solid dispersion by
increasing molecular mobility and it result into the development of crystal growth. Spray
drying process carried out at a lower outlet temperature gives a product with high residual
solvent levels and poor flow property [65-67].
Mass and co-workers [68] have prepared 15% aqueous solution of mannitol and
spray dried it at 3 different temperatures i.e. 60°C, 90°C and 120°C (M60, M90, and
M120). They observed that at 60°C outlet temperature, mannitol particles were more
spherical without inside void spaces or hole formation as compared to particles dried at
90°C and 120°C. They concluded that due to lower internal pressure applied by the
evaporating liquid at 60 °C than at 90 °C and 120 °C, giving the vapor sufficient time to
escape without rupturing the solid shell [68]. Likewise, Paramita and coworkers have also
found that spray-dried powders at higher outlet temperatures give higher % of hollow
particles [69].
2.1.9 Effect of various formulation additives on product characteristics
The development of solid dispersion is shifting towards the addition of a third or
even more components along with polymeric carrier (so called as ternary solid dispersion)
to stabilize the amorphous form of drug during storage. The most commonly used
adjuvants are surfactants or co-solvents that are added in the solid dispersion to improve
the dissolution and physical stability of drug by improving the wettability and minimize
the crystallization of drug during storage. Apart from surfactant, glidants/drying agents
are also added during spray drying process to improve the flow property and yield of the
powder and to minimize sticking tendency of particle in spray drying chamber. Some
other additives can also be added in spray drying process like disintegrants, pH modifiers,
salt former, complexing agents, etc.[70-75].
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 30
2.1.9.1 Effect of silica on product characteristics
The use of colloidal silica can minimize the electrostatic charge generation
between powders with the spray dryer wall, leading to increased yield as well as
improved flow property of powder. Moreover, porous silica also works as adsorbents
(which gives more surface area) and playing a significant role in solubility enhancement
[76-77]. Palninsek and co-workers [78] have developed solid dispersion containing
porous silica and observed that porous silica plays a significant role in solubility
enhancements. Pokharkar and team have also accomplished that the stability of solid
dispersion was significantly improved due to addition of Aerosil®
200 [79]. Ambike and
team have also found that silica was playing a significant role in improvement of flow
property and stability of low glass transition temperature (Tg) drug like Simvastatin [80].
Similarly, Chauhan and co-workers [81] have prepared spray dried solid dispersion in
presence of Aerosil®
200 as adsorbents and found improvement in dissolution rate (even
after 3 months storage) as well as bioavailability. Numerous other research works have
also been reported about improvement in dissolution, process yield and stability after
addition of silica in spray drying feed solution [82-84].
2.1.9.2 Effect of lactose on product characteristics
Makai and team [85] have evaluated the effects of lactose on the surface
properties of microparticles prepared by a spray-drying method. In this work, they
compared 3 different formulations of untreated microcrystals, alginate-based spray-dried
microparticles and alginate-based lactose containing spray-dried microparticles of
trandolapril. They observed faster dissolution for the sample containing lactose in
comparison to those samples containing alginate or alginate and lactose. Moreover, they
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 31
concluded that the application of lactose caused a marked increase in the surface polarity
of the particles which helps to increase the solubilization potential of drug.
2.1.9.3 Effect of stabilizer on product characteristics
The amorphous form of drug has the highest free energy and entropy which
results in superior molecular motion compared to the crystalline state (leading to higher
apparent solubility and dissolution rate). High internal energy and molecular mobility of
amorphous materials are also accountable for crystallization during storage and it can be
minimized by addition of suitable and proper concentration of stabilizer [86-87]. So,
stabilization of amorphous form of drug during storage is more important to improve the
dissolution and in vivo efficacy of developed formulation.
In various research studies, scientists have used different stabilizers or surfactants
along with drug-polymer mixtures to improve the stability of solid dispersion. Beck and
co-workers [88] have used non-ionic surfactant Pluronic F127 as a stabilizer for the
HPMC based solid dispersion. They observed that the addition of Pluronic F127 along
with HPMC results in controlling initial growth and suppression of agglomeration and the
optimal formulation results in faster and higher extent of dissolution than a poorly
stabilized suspension.
2.1.10 Scale-up in spray drying
Spray dryers in the pharmaceutical industry are available in a wide range of
scales: from lab scale to commercial scale which is capable of handling several tons of
material per day [89]. Comparison of spray dryer at laboratory, pilot and commercial
scales is shown in Table 2.5 [35, 91].
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 32
Table 2.5 Comparison of spray dryer at laboratory, pilot and commercial scale
[Reference: 35, 91]
Parameter Lab scale Pilot scale Commercial
scale
Drying gas Nitrogen / Air
Type of feed Aqueous/organic solutions, suspensions or emulsions
Fit for injectables? Yes Yes Yes
Atomization devices 2-fluid nozzle 2-fluid nozzle,
Pressure nozzle
2-fluid nozzle,
Pressure nozzle
Nominal drying gas flow
(kg/h)
40 80 1250
Feed flow rate (kg/hr) 2.5 45 45-60
Outlet temperature (°C) 40 to 65 40 to 65 40 to 65
Evaporating capacity (kg
water/h)
1 6 90
Typical batch scale (kg) 0.01 – 0.500 0.2 - 20 10 - 1000
Proper optimization of process parameters using factorial design is very powerful
tool to support the scale-up of spray drying process to achieve the desired powder
characteristics at larger scale. The use of process simulation tool can also give robust
processes, faster development at a lower cost and high product quality [90]. Influence of
four main parameters like as inlet temperature, feed flow rate, atomization gas flow rate
and solid concentration in feed solution should be evaluated properly in the lab scale
development. The effects need to be determined in terms of particle size, morphology,
residual solvent, crystallanity, yield and stability. In order to accomplish the uniform
particle size in production scale, atomization gas flow and feed rate also need to be
optimized (like high atomization gas flow and low feed rate gives smaller particles in
production scale spray dryer) [91]. Selection of suitable nozzle type depends on the target
quality attributes and properties of feed solution. In most pharmaceutical applications,
pressure nozzles are preferred then 2-fluid nozzles, because they provide powders with a
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 33
narrow particle size distribution. In literature, it was also reported that the lab scale
atomizer are typically 2-fluid nozzle, which are replaced by a pressure nozzle in the
commercial scale to control the particle size [92-94].
2.1.11 Characterization of amorphous solid dispersion after spray drying process
Conversion of API from amorphous to crystalline form during storage may results
into solubility retardation. So, determination of glass transition temperature of carrier,
molecular mobility of the drug and the rate and extent of drug crystallization, etc., need to
be evaluated accurately to study the effect of storage on solubility of drug. A wide range
of thermal analytical techniques can be used for characterization of solid dispersion and
among it, differential scanning calorimetry (DSC) is generally available in many
industrial and academic laboratories [9, 16 and 95].
A modest factor like presence of moisture in DSC instruments can also affect the
Tg of solid dispersion which was previously reported by crowley and zografi [96], as they
have evaluated the absorption of moisture by various solid dispersions and concluded that
Tg was strongly depressed by absorption of moisture. Konno and taylor [97] have also
studied the plasticizing effect of the moisture and they observed that in the absence of
moisture, the Tg of solid dispersion was increased toward the direction of the Tg of the
pure polymer. While, in the presence of moisture, the Tg values of the dispersions were
lower, which clearly indicate that presence of moisture enhances the molecular mobility
of polymer and reduces the Tg value in PVP based solid dispersion.
Some other thermal analytical techniques used are X-Ray Diffractometry (XRD),
for identification of crystalline structure in solid dispersion. In XRD spectra, crystalline
form of drug usually shows sharp peaks as specific 2θ angles while amorphous form
shows a halo peak and so both polymorphic forms can be easily differentiated from each
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 34
other. Similarly, presence of single Tg peak of polymer without sharp melting peak of
drug in DSC spectra for solid dispersion indicates that degree of crystallinity is
considerably reduced and the drug is present in amorphous form [98].
2.1.11.1 Determination of Tg by interpreting of thermal DSC spectra
A typical DSC spectrum is shown in Figure 2.5, mostly 2 kinds of heat flows are
observed during DSC experiments, either endothermic (heating) or exothermic (cooling)
peak. In general, endothermic heat flows occur during processes like glass transition,
melting, evaporation, etc., while exothermic heat flows occur during processes like
crystallization, degree of cure, oxidation, etc. To understand DSC thermal spectrum, it
requires a good amount of experience in thermal analysis as well as knowledge of
probable chemical reaction that solid dispersion kind of system generally pursue [99]. Tg
is the accepted short form for the glass transition temperature. All amorphous (non-
crystalline or semi-crystalline) materials will yield a Tg and it provide very valuable
information concerning the performance of a product. The glass transition phenomenon
occurs when a hard, solid, amorphous substance or component undergoes its
transformation to a soft, rubbery, liquid phase [100]. Right practical method to calculate
the Tg of polymer from DSC spectra is shown in Figure 2.6.
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 35
Figure 2.5 Typical differential scanning calorimetry (DSC) spectrum
Figure 2.6 Practical methods for determination of Tg from DSC spectrum
2.1.11.2 Instruments handling and factors to be considered during DSC analysis
A variety of factors that may cause incorrect interpretation of DSC spectra like
calibration of instrument before sample run, selection of pan (like crimped or hermetic
pan), previous sample contamination in pan, sample preparation – how sample is loaded
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 36
into a pan, residual solvents and moisture, environmental moisture present in DSC
instrument, sample quantity taken for analysis, processing errors, etc. Sample should be
kept as thin as possible and covered properly as much as of pan bottom surface to
minimize thermal gradients. Sample size in DSC should also be considered because more
quantity of samples will increase sensitivity but it may decrease resolution. Moreover, if
the peak resolution of Tg is very weak, increase in the sample size may help to get more
clear peak interpretation. Heating rate should also be considered as faster heating rates
increase sensitivity but it also decreases resolution. So, good starting point is a heating
rate of 10°C/min. Other factors to be considered are to run flush out gases (such as
nitrogen, helium or compressed air) during DSC experiments to provide dry and inert
atmospheres, ensure even heating and help to sweep away gases that might be released,
etc. [101-103].
2.1.12 Quality by design (QbD) in spray drying
QbD can be defined as to design a process in such a way that final product meet
all the predefined specification and achieve desirable quality attributes. In recent times,
there is an increasing demand from regulatory authorities to implement QbD and design
of experiment (DoE) methodology in product development stage. Objective behind this
initiative is to understand the manufacturing processes together to achieve final product
within predefined excellence [104]. International conference on harmonization (ICH) has
published guidelines that “the aim of pharmaceutical development is to design a quality
product and its manufacturing process to consistently deliver the intended performance of
the product. The information and knowledge gained from pharmaceutical development
studies and manufacturing experience provides scientific understanding to support the
establishment of the design space, specifications, and manufacturing controls” [105]. So,
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 37
identification of critical quality attributes (CQA) and critical process parameters (CPP) in
spray drying are more needed to study the effect of their variation on the quality of final
product. The FDA’s process analytical technology (PAT) initiative is also one of the
collaborative efforts and the aim of PAT is similar in line with QbD to assure high
product quality through timely measurements of critical quality and performance
attributes of raw materials, in-process materials and final products [106].
By considering the complexity of spray drying process, optimization of spray
drying process parameters is quite challenging to achieve the desirable product. In one of
the research work, Amaro and co-workers [107] have applied 24 factorial DoE and
studied various CPPs like inlet temperature, gas flow rate, feed solution flow rate and
feed concentration. They have evaluated resulting powders in terms of yield, particle size
(PS), residual solvent content (RSC), specific surface area and outlet temperature as
CQA. They observed that the yield was increased with a decrease in gas flow and it
remains unchanged with respect to increasing or decreasing the inlet temperature [107].
Similar observation was also further supported by Buchi documents that lower gas flow
reduces atomization energy and produces larger particles [108]. Baldinger and team had
illustrated the influence of CPP on CQA of spray-dried powders by applying DoE and
found that the full factorial design proved to be unsuitable due to the non-linear influence
of factors while the composite face-centered design improved the quality of the models
and showed both linear and non-linear influence of the parameters on the outcomes [109].
Prinn et al [110] and Maltesen et al [111] have found that feed solution
concentration has the higher impact than gas flow rate on process yield. Büchi technical
data also demonstrated that gas flow and feed solution concentration have a largest
influence on the resulting particle size [108]. Lower gas flow reduces atomization energy
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 38
and producing larger particles [112, 108]. Maury and coworkers have observed that the
powder yield was increased at higher process temperatures, due to improved droplet
drying and reduced droplet/particle deposition on the walls of the drying chamber [113].
Particle size is also one of the most important CQA in spray drying process and there are
a number of reports indicating that as gas flow decreases and feed concentration increases
larger particles are produced [112,114-115].
Residual solvent content is also one of important evaluation parameter in spray
drying process as residual solvent work as plasticizer to reduce the Tg and may convert
amorphous form of dug to crystalline form during storage. Amaro and coworkers have
observed that with increasing inlet temperature, more energy is supplied to the drying
chamber leading to more efficient solvent removal from the droplets which reduces
residual solvent in the powder [107]. Maury and team have observed that high feed rate
generates more solvent vapor and reduces the exhaust temperature leading to a less
efficient drying, hence higher residual solvent content [113]. So, in order to achieve
higher yield with less residual solvent content, high outlet temperature is required
[107,115].
Another important evaluation parameter in spray drying process is the porosity
and specific surface area (SSA) of microparticles [107]. Porous microparticles have
potential advantages over non-porous materials as they have less inter-particulate
attractive forces with better flow characteristics, and exhibit smaller aerodynamic
diameters than their geometric diameters, facilitating greater deposition in the lower
pulmonary region, with improved efficiency [116-117].
Amaro and co-workers have observed that 3 major CPPs have a negative effects
i.e. inlet temperature, feed rate and feed concentration, indicating that when any of these
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 39
factors decrease, particles with higher surface area are produced. One major CPP has a
positive coefficient i.e. gas flow, giving particles with higher surface area at higher levels
[107].
Cabral-Marques and Almeida have also developed and characterized a
beclomethasone: γ-cyclodextrin complex and optimized the variables on the spray-drying
process to obtain a powder with the most suitable characteristics for lung delivery [118].
All of above research work highlights the complexity of process and interaction of spray
drying process parameters in the final quality of product. So, proper design of
experimental is required in spray drying process to achieve a powders with desirable
characteristics, i.e. high yield, uniform particle size, high surface area and low residual
solvent.
2.1.13 In vitro - in vivo correlation (IVIVC) of spray dried formulation
After preparing amorphous solid dispersion by spray drying technology, in vitro
dissolution as well as animal or human in vivo absorption study is requires for complete
understanding. Poddar and his team [119] have prepared solid dispersion of ritonavir
using polyvinyl pyrollidone vinyl acetate as a carrier polymer for solubility enhancement.
During in vitro dissolution analysis, they observed that 95% of drug was released in 25
min from solid dispersion while only 20% of drug was released in 60 min from physical
mixture. In vivo bioavailability results showed AUC (t-8 h) value of 59.62 µg/mL hr for
solid dispersion compared with that of pure drug which was 8.08 µg/mL hr. This result
suggested that the absorption rate of solid dispersion was remarkably higher than pure
drug and they concluded that prepared solid dispersion could significantly improve both
the dissolution rate and bioavailability of ritonavir.
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 40
Patel et al. [120] have prepared the solid dispersion of fenofibrate with poloxamer
407 using spray drying technology. The spray dried particles were characterized for the in
vitro dissolution studies and in vivo absorption studies and the results showed that the
dissolution rate and oral bioavailability of the spray dried fenofibrate/poloxamer 407
particles were significantly increased as compared to pure drug. They concluded that
improved particle wetting in presence of the hydrophilic surfactant (as evidenced by
contact angle measurements) seems to be the most important determinant for in vivo oral
bioavailability. Muttil et al. [121] have prepared biodegradable and inhalable
microparticles containing anti-tuberculosis drugs using spray drying technology. During
in vivo studies they found that drug concentrations in macrophages were ~20 times higher
when microparticles were inhaled rather than drug solutions administered. Naikwade et
al. [122] have investigated the in vivo efficacy of budesonide (BUD) microparticles for
pulmonary administration and found that developed formulations had extended half-life
(14 hr) compared to conventional formulation (9 hr) with one to four-fold improved
systemic bioavailability with excellent lung deposition.
Table 2.6 List of commercial formulation prepared using solid dispersion technology
[12]:
Product API name BCS
class
Polymer Manufacturing
method
Dosage
form
Approval
Year
Kaletra®
Lopinavir/
Ritonavir
IV PVP/VA Melt Extrusion Tablet 2005
Norvir®
Ritonavir IV copovidone Melt extrusion Tablet 2010
Fenoglide®
Fenofibrate II PEG Melt extrusion Tablet 2007
Implanon®
Etonogestrel EVA Melt extrusion Rod 2006
Prograf®
Tacrolimus II HPMC Spray drying/fluid bed Capsule 1994
Sporanox® Itraconazole II HPMC Spray drying Capsule 1992
Cesamet®
Nabilone II PVP Spray drying Capsule 2006
Intelence®
Etravirine IV HPMC Spray drying Tablet 2008
Nimotop® Nimodipine II PEG Spray drying/fluid bed Capsule 2006
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 41
2.1.14 Table 2.7 List of US patent issued using spray drying technology. Ref:
www.uspto.org (updated till Nov 5, 2012)
Title of patent Patent No publication
date/year
Effervescent dipeptide sweetner tablet US 4,009,292 Feb. 22,
1977
Process for making a spray dried, direct
compressible vitamin powder comprising un-
hydrolyzed gelatin
US 4,892,889 June 9,1990
Nimesulide salt cyclodextrin inclusion
complexes
US 5,744,165 A Apr. 28,
1998
Method for making porous microparticles by
spray drying
US 5,853,698 A Dec. 29,
1998
Solid coprecipitates for enhanced bioavailability
of lipophilic substances
US 5,891,469 A Apr. 6, 1999
Preparation of diagnostic agents by spray drying US 6,344,182 B1 Feb. 5, 2002
Method of spray drying pharmaceutical
composition
US 6,565,885 B1 May 20,
2003
Method for making homogeneous spray- dried
solid amorphous drug dispersions utilizing
modified spray dried apparatus
US 6,763,607 B2 Jul. 20, 2004
Inhaleable spray dried 4-helix bundle protein
powders having a minimized aggregation
US 6,838,075 B2 Jan 4, 2005
Alprazolam inclusion complexes and
pharmaceutical composition thereof
US 7,202,233 B2 Apr. 10,
2007
Amorphous substance of tricyclic
triazolobenzazepine derivative
US 7,229,985 B2 Jun. 12,
2007
Method for making homogeneous spray- dried
solid amorphous drug dispersions using pressure
nozzles
US 7,780,988 B2 Aug. 24,
2010
Pharmaceutical compositions comprising drug
and concentration enhancing polymers
US 7,887,840 B2 Feb. 15,
2011
Solubilizing aids in powder form for solid
pharmaceutical presentation forms
US 7,906,144 B1 Mar. 15,
2011
Porous drug matrices and method of
manufacturing thereof
US 7,919,119 B2 Apr. 5, 2011
Preparation method for solid dispersion US 8,216,495 B2 Jul. 10, 2012
Enhancing solubility of iron amino acid chelates
and iron proteinates
US
20030069172A1
Apr. 10,
2003
Pharmaceutical composition containing polymer
and drug assemblies
US
20030170309A1
Sep. 11,
2003
Pharmaceutical composition for solubility
enhancement of hydrophobic drugs
US20050008704A1 Jan. 13,
2005
Spray dried process for forming solid
amorphous dispersion of drug and polymers
US20050031692A1 Feb. 10,
2005
Basic drug compositions with enhanced US20050049223A1 Mar. 3, 2005
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 42
bioavailability
Benzoquinones of enhanced bioavailability US
20070026072A1
Feb. 1, 2007
Amorphous efavirenz and the productions
thereof
US
20070026073A1
Feb. 1, 2007
Solid compositions of low solubility drugs and
poloxamers
US
20070141143A1
Jun. 21,
2007
Stabilized pharmaceutical solid compositions of
low-solubility drugs and Poloxamers and
stabilizing polymers
US
20070148232A1
Jun. 28,
2007
Amorphous ezetimibe and the production
thereof
US
20080085315A1
Apr. 10,
2008
Amorphous valsartan and the production thereof US
20080152717A1
Jun. 26,
2008
Carotenoids and enhanced bioavailability US
20080181960A1
Jul. 31, 2008
Amorphous oxcarbazepine and the production
thereof
US
20080181961A1
Jul. 31, 2008
Use of dry powder composition for pulmonary
delivery
US
20080202513A1
Aug. 28,
2008
Amorphous varenicline tartrate and process for
the preparation thereof
US
20090318460A1
Dec. 24,
2009
Spray dried formulation US
20100029667A1
Feb. 4, 2010
Aerosolized fluoroquinolones and uses thereof US
20100166673A1
Jul. 1, 2010
Enhanced delivery of immunosuppresive drug
composition for pulmonary drug delivery
US
20100183721A1
Jul. 22, 2010
Dosage form comprising celecoxib providing
both rapid and sustained pain relief
US
20100233272A1
Sep. 16,
2010
Encapsulated particles for amorphous stability
enhancement
US
20100297248A1
Nov. 25,
2010
Solubility enhanced form of aprepitant and
pharmaceutical composition thereof
US
20110009362A1
Jan. 13,
2011
Oral solid dosage form containing
nanoparticlesand process of formulating the
same using fish gelatin
US
20110064812A1
Mar. 17,
2011
Fenofibrate formulation with enhanced oral
bioavailability
US
20110160274A1
Jun. 30,
2011
Composition containing lipid micro or
nanoparticles for enhancement of the dermal
action of solid particles
US
20120128777A1
May 24,
2012
2.1.15 Table 2.8 Application of spray drying technology for pulmonary & nasal delivery
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 43
Area of
application
Drug Specific advantage Ref.
Pulmonary
delivery
Tobramycin Great potential for treating diseases that
require direct lung delivery with reduced
drug dosage and dosing frequency, fewer
systemic side effects.
[123]
Pulmonary
delivery
Itraconazole Processing of nanoparticles with mannitol
and 10% leucine could significantly improve
the aerosolization properties of itraconzole.
[124]
SR
microsphere
for pulmonary
delivery
Terbutaline
sulphate
Hydrogenated palm oil demonstrated SR
barrier properties. Fine particle fractions of
the aerosolized dry powder were acceptable
and would correspond with effective lung
deposition in areas beyond the mucocilliary
escalator
[125]
Lung delivery Sodium
Alendronate
The intratracheal administration of sodium
alendronate dry powder results in a
6.23±0.83% bioavailability, a 3.5-fold
increase as compared to oral bioavailability
[126]
Pulmonary
protein
delivery
Insulin NPs were co-spray dried with mannitol
shows a dry powder with adequate
aerodynamic properties
[127]
Pulmonary
drug delivery
Coumarin 6,
Sildenafil
Spray-dried polymeric particles reveal
prolonged drug release properties and shows
prolong lung deposition
[128]
Dry powder
inhaler (DPI)
Gelatin Gelatin nanoparticles can be loaded with
active principles like drugs, peptides,
oligonucleotides for systemic delivery in
lung
[129]
Pulmonary
delivery
Salbutamol
sulphate
The resulting powders exhibit a large surface
area and a low bulk density. The main
excipient utilized for the particle formation is
hydrated phosphatidylcholine.
[130]
Pulmonary
delivery
Insulin Powder having an increased particle fraction
smaller than 2µm and insulin may reach the
deeper lung for better absorption and
therapeutic action.
[131]
Pulmonary
delivery
β-Galactosidase The protein exhibited higher storage stability
when spray dried without ethanol and when a
larger spray cap size was used
[132]
Pulmonary
delivery
Budesonide Nanoporous microparticles od Budesonide
shows improved aerosolisation properties
and showed a reduced tendency to
recrystallise during stability.
[133]
Pressurized
dry powder
Inhaler
Alkaline
phosphatase
Co-spray-drying proteins and peptides with
NaCMC may offer an alternative method for
the preparation of stable and respirable pMDI
[134]
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 44
Pulmonary
delivery
Ciprofloxacin
Hydrochloride
The combination formulation containing
50% (w/w) mannitol appeared to have the
best aerosol performance, good stability and
lowest particle cohesion
[135]
Pulmonary
delivery
Cetrorelix-
acetate (peptide)
The pearl milled cetrorelix showed
promising results when delivered by the
Novolizer: a reproducible and highly
efficient dispersion of the drug was achieved
(around 60% drug loading). The spray dried
drug was not suitable when processed as
adhesive mixture.
[136]
Dry powder
for Inhalation
(DPI)
Humanized
monoclonal
antibody (IgG1)
Protein stabilization was improved by the
addition of glycine but trehalose and sucrose
were most effective in preventing
aggregation. Isoleucine also shows positive
effects on both flowability and protein
stability
[137]
Dry powder
for Inhalation
Terbutaline
sulphate
The adhesion of terbutaline sulphate on the
lactoses tested was found lower
[138]
Dry powder
for Inhalation
Naringin
(flavanoids)
Spray-drying seems to provide a amorphous
powders with controlled shape & respirable
size.
[139]
Pulmonary dry
powder
vaccine
Diphtheria–
tetanus–pertussis
It can improve the stability, removing cold
chain storage complications associated with
conventional liquid-based vaccines.
[140]
Pulmonary
protein
delivery
Therapeutic
protein
Microspheres were spherical with good
aerodynamic properties like 2–3 µm
diameters and low tap density and 68% drug
loading.
[141]
Nasal delivery Gentamicin
sulfate
All the microspheres were at a suitable size
and had good mucoadhesive property for
nasal administration.
[142]
Nasal delivery Influenza
vaccine
The viscosity-enhancing capacity of carbopol
and the irritating capacity of poly (acrylic
acid) might have an adjuvant function in
obtaining the high immunological response.
[143]
Nasal delivery Ondansetron
HCl
Microspheres of ondansetron hydrochloride
with mucoadhesive property shows increased
bioavailability
[144]
Nasal delivery Human immuno
globulin IgG
The addition of leucine to the spray-drying
solution, or a physical blend with Aerosil®,
may have enhanced nasal deposition.
[145]
Nasal Delivery Zolmitriptan Narrow particle size and high drug loading
with chemically stable powder obtained after
spray drying process
[146]
Nasal delivery Metoclo-
pramide
Microparticles based on MPC are shows
better muco adhesiveness, less swelling
capability and prolonged ex-vivo permeation
profile than particles containing chitosan.
[147]
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 45
2.1.16 Table 2.9 Review of solid dispersion prepared via spray drying technology in
literatures
Drug Carrier(s) Application of spray drying method Ref
Atorvastatin Pure drug spray
drying
Conversions of crystallization to
amorphous form improve solubility.
[148]
Fenofibrate HPMC E3 and
DOSS
Improvement in solubility [149]
Acyclovir Chitosan,
tripolyphosphate
Microparticles with improved drug
solubility
[150]
Albendazole HPMC and PVP Solubility enhancement [151]
Fenofibrate Poloxamer 188,
TPGS
Solubility enhancement of fenofibrate [152]
Ibuprofen Poloxamer 127 Improve the drug dissolution of
Ibuprofen
[153]
Itraconazole HP β-CD Improve the dissolution of iraconazole [154]
Lycopene Gelatin and
sucrose
Sustained release microcapsule of
lycopene
[155]
Cyclosporin PLGA (85:15) Controlled release biodegradable
nanoparticle
[156]
Atenolol,
Metoprolol
Nano fibrillar
cellulos
Sustained release microparticles with
spherical shape around 5µm
[157]
Piroxicam Pure drug Direct compressible powder with
improved dissolution
[158]
Bovine serum
albumin
Tween 80 Protein nanoparticles prepared for a
variety of drug delivery applications
[159]
Diphenhydramin
e
HPMC and PVP Taste masking application [160]
Diltiazem EUDRAGIT®
RS 100 & RL
100
Sustained release microparticles [161]
Itraconazole EUDRAGIT® E
100
Dissolution and solubility enhancement [162]
Loperamide PEG 6000 Solubility enhancement [163]
Tacrolimus HP-β-CD and
DOSS
Improved solubility about 900-fold and
dissolution of tacrolimus 15-fold
[164]
Tacrolimus EUDRAGIT® E
PO
Solubility enhancement of tacrolimus [165]
Flurbiprofen Hsp-G 2.5- and 2.8-fold improvement in the
Cmax and AUC values
[166]
Naringenin,Quer
cetin
CAP Gastric protection with improved
dissolution in pH 6.8 phosphate buffer
[167]
Bicalutamide HPMC Improvement in dissolution rate [168]
Irbesertan PVP K30 Significant enhancement of stability and
dissolution
[169]
Buspirone EUDRAGIT®
RS 30 D
Sustained release microparticle drug
delivery
[170]
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 46
Pioglitazone Poloxamer 407
HP-β-CD
Dissolution enhancement of pioglitazone [171]
Roxithromycin HPMC and
Sodium CMC
18 times faster dissolution of
roxithromycin
[172]
Valdecoxib PVP K-30 and
HPC
Improvement in the solubility,
dissolution rate and suppressing
crystallinity
[173]
Bovine Insulin PLGA Successful encapsulation of Insulin in
PLGA microspheres
[174]
Small interfering
(Si) RNA
PLGA 75:25 Integrity and biological activity of
siRNA can be preserved and useful for
inhalation therapy
[175]
Vancomycin
(Peptide)
PLGA Resomer
RG 502H
Good encapsulation efficiency and 2 fold
increase in AUC for ocular delivery
[176]
Abbreviation: PVP: Polyvinyl pyrrolidone; HPMC: Hydroxypropyl methyl cellulose;
HPC: Hydroxy propyl cellulose; HP-β-CD: hydroxypropyl- β- cyclodextrin; CAP:
Cellulose acetate phthalate; DOSS: Dioctyl sulfosuccinate; PLGA: Poly (DL-lactideco-
glycolide); IPA: Isopropyl alcohol; DCM: Dichloro methane; Tween 80: Polyoxy
ethylene sorbitan monooleate; CMC: Carboxy methyl cellulose; PVA: Polyvinyl alcohol;
PEG: Polyethylene glycol; PG: Propylene glycol; Hsp-G: α- Glucosyl hesperidin; THF:
Tetrahydro furan; TPGS: (d-alpha tocopheryl polyethylene glycol 1000 succinate); AUC:
Area under curve
2.1.17 Table 2.10 Spray drying application in other than pharmaceutical industry
Area of
application
Specific advantage/ outcome of research work Ref.
Microencapsulation
of peppermint oil
Highest flavor retention with gum arabic and the (1:1)
blend (81%)
[177]
Amaranthus
Betacyanin
pigments
Adding maltodextrins and starches reduced the
hygroscopicity of the betacyanin extracts and enhanced
stability.
[178]
Microencapsulation
of l-manthol oil
Gum arabic acid seemed to be more suitable for
encapsulating l-menthol as compared to modified starch
[179]
Encapsulation of
lipid based
vegetable oil
(aromas)
Oil drops were well dispersed within the solid matrix and
only 1.2% of the total oil content was found unprotected
and during accelerated oxidation test, oil oxidation was
reduced.
[180]
Microencapsulation
of linseed oil for
nutraceutical use
Microcapsules made of 100% GA and mixtures of GA,
MD and WPI presented highest protection from oxidation
and efficiencies was higher than 90% with 10 months
stability.
[181]
Conversion of the
liquid bayberry
juice into powder
No powder was recovered when the bayberry juice was
spray dried alone. Addition of protein (1%) and
maltodextrin (30%) gives powder recovery more than
50%.
[182]
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 47
Microencapsulation
of extract of guava
fruit juice
The use of AG improves the fluidity during the drying
but produces an undesirable residual taste and decreases
the thermal stability of final microencapsulated powders.
[183]
Microencapsulation
of passion fruit
(Passiflora) juice
N-Octenylsuccinate-derivatised starch showed good
encapsulation of passion fruit juice, and capable of
retaining vitamin C during a long time of storage.
[184]
Microencapsulation
of epigallo catechin
gallate
EGCG microparticles produced by low temperature can
maintain high antioxidant activity.
[185]
Production of a
red–purple food
colorant (Opuntia
fruits)
Color was retained during the drying process (>98%) and
yield was high (58%). The powder colorant showed high
color strength and stable at room temperature for 1
month.
[186]
Microencapsulation
of lycopene powder
Ratio of gelatin/sucrose as 3/7 showed good purity and
sphericity of lycopene powder (52%) with good storage
stability.
[187]
Spray drying of
Sumac flavour
(extraction of
sumac berries)
sodium chloride observed appropriate under the
conditions of the spray-dryer. Sucrose and glucose caused
caramelization while starch caused problem such as
clogging the nozzle.
[188]
Spray drying of
brewer’s yeast
Various factors were optimized like initial product
moisture, input air and dry air to achieve10 kg dried yeast
per h.
[189]
Spray drying of
tomato pulp
Product recovery increased with increases in drying air
flow rate, in air inlet temperature and in compressed air
flow rate.
[190]
Microencapsulation
of macadamia oil
Sodium caseinate:maltodextrin at 1:4 ratio with feed rate
of 1.1 kg/h and inlet temperature at 167°C showed good
powder yield.
[191]
Microencapsulation
of fish oil
Combination of 10% SSPS and 65% OSA gives a good
encapsulation efficiency with a shelf life of 5 weeks at
±21 °C.
[192]
Production of
instant soymilk
powder
10% w/v maltodextrin gives largest particle size (260 µm)
having a good flowability, dispersibility and low
cohesiveness.
[193]
Heat-stable
measles vaccine
produced by spray
drying
l-arginine, human serum albumin, and a combination of
divalent cations are key stabilizer for the preparation of
dried vaccine which is stable for up to 8 weeks at 37 °C.
[194]
Influenza subunit
vaccine powder for
inhalation
PBS is preferred for better stabilization of vaccine.
Vaccine was stable for at least 3 years at 20 °C with good
particle size distribution and immunogenicity after i.m
administration.
[195]
Microencapsulation
of bifidobacteria
Results showed that the oligofructose-enriched inulin is
the most suitable prebiotics in spray drying process of
bifido bacteria.
[196]
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 48
2.1.18 Summary of literature review
The new molecules synthesized by various pharmaceutical companies or even
existing molecules from certain therapeutic classes such as antiretroviral drugs turn out to
be of low aqueous soluble in most cases. So, there is a need for a formulator to find a
solution though different formulation designs and among it binary or ternary amorphous
solid dispersion approach have proven to overcome such solubility issues of BCS class II
and IV molecules. Out of various technologies to generate solid dispersion/solution, spray
drying method is constantly gaining attention due to its ease of processing thermo labile
compounds, its flexibility in terms of wide application range (taste masking, solubility
enhancement, uniform particle size for pulmonary drug delivery, etc) and the ease on
process control to achieve final powder characteristics in terms of particle size
distribution, flow property, porosity, yield, etc. A deep insight into the critical process
parameters of the spray drying technology is important to obtain the desired product
quality. Carrier polymer is a critical component in spray drying process because it not
only increases the solubility of poorly water soluble drug but also plays a vital role in
minimizing the crystallization of drug during storage. So, successful and efficient
polymer screening method like MEMFIS mathematical tool might be one of the best
options to identify solubility-enhancing polymer without or with very limited
consumption of drug. Moreover, a proper understanding of various thermo analytical
methods like DSC and XRD are also very important to understand the desired solid state
characteristics of solid dispersions for identification of Tg and crystallinity of polymer. In
recent times, there is an increasing demand from regulatory authorities to implement QbD
and DoE methodology during product development. By considering the complexity of
spray drying process, identification and optimization of CPP and CQA in spray drying
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 49
process parameters is required to achieve a powder with desirable quality attributes such
as high yield, uniform particle size, high surface area and low residual solvent.
2.1.19 Conclusion of literature review
Most of NCEs discovered by the pharmaceutical researchers are poorly soluble in
nature and they required solubility enhancement to achieve desired bioavailability and
therapeutic efficacy and which can be obtained by use of spray drying based solid
dispersion technology. Solubility enhancement in spray drying method is mainly due to
conversion of crystalline form to amorphous form in presence of carrier polymer and the
amorphous form of drug is associated with a higher energy state as compared to
crystalline counterpart and due to that it required very less external energy to dissolve.
Major challenge for formulation scientist in spray drying technology is to accomplish a
long term stability of amorphous form of drug. In order to achieve a long term stability,
selection of right polymeric carrier is required which can form a molecular solid glassy
solution by decreasing the molecular mobility of the drug and due to that it reduces the re-
crystallization of drug during storage. So, currently there is a frequent need in
pharmaceutical industry to do more brain storming to develop some advanced
technologies which can screen out the suitable polymeric carrier to achieve a stable solid
dispersion. By considering the limited quantity of drug available in the early stage of
NCE development, MEMFIS mathematical tool might be one of the preferences to
identify solubility-enhancing polymer without consumption of drug. Moreover, spray
drying process involves interactions between various formulation variables (like feed
concentration, solvent type, type of polymer) and process conditions (drying gas flow
rate, feed rate, outlet temperature, atomization rate) which can significantly influence the
particles characteristics (yield, particle size, residual solvent content, flow property,
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 50
surface area and release profile) of the solid dispersion. Based on the recent FDA and
ICH product development guidelines, Quality by Design (QbD) should also be adopted in
spray drying formulation development to achieve the product within predefined quality
specification. By considering the complexity of spray drying process, factorial design
models can also be put together to optimize the CPP which can produce a powder with
suitable characteristics, i.e. high process yield, maximum dissolution, uniform particle
size with low residual moisture content. It is also important to understand the factors
influencing scale-up of spray drying process. Accurate understanding of various thermal
analytical technologies like DSC and XRD with instrument handling knowledge is also
vital for proper characterization of solid dispersion.
2.1.20 Table 2.11 Highlights
• Solubility of drug plays vital role in achieving desired therapeutic effect and
amorphous solid dispersions are developing as a platform to overcome the poor
solubility and bioavailability issue of BCS class II and IV molecules.
• Customized particle characteristics obtained after spray drying process makes it
more useful in pharmaceutical industry for various application.
• Amorphous form of drug in solid dispersions are physically and chemically less
stable than crystalline form and, therefore during storage, it may convert to
crystalline form which retards the solubility. So, in-depth knowledge about various
analytical studies like DSC and XRD is required for determination of Tg and extent
of drug crystallization to study the effect of storage on solubility of drug.
• Quality by design (QbD) approach must be adopted for spray drying technology to
study the effect of various formulation variables (feed concentration, solvent type,
carrier) as well as CPPs (drying gas flow rate, feed rate, outlet temperature) on CQA
(porosity, particle size, flow, surface charge, release profile) to achieve the desired
robust product quality.
• It is also quite essential to understand the factors influencing scale-up of spray
drying process for easy commercialization from lab scale to production scale.
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 51
2.1.21 References
1. Shukla D, Chakraborty S, Singh S, Mishra B. Lipid-based oral multiparticulate
formulations - advantages, technological advances and industrial applications. Expert
Opin Drug Deliv 2011;8:207-24
2. Giri TK, Alexander A, Tripathi DK. Physicochemical classification and formulation
development of solid dispersion of poorly water soluble drugs: an updated review. Int J
Pharm Bio Arch 2010;1:309-24
3. Kumar A, Sahoo SK, Padhee K, et al. Review on solubility enhancement techniques for
hydrophobic drugs. Int J Comp Pharm 2011;3:1-7
4. Verma S, Rawat A, Kaul M, Saini S. Solid dispersion: A strategy for solubility
enhancement. Int J Pharm Tech 2011;3:1062-99
5. Patel TB, Patel LD. Formulation and development strategies for drugs insoluble in gastric
fluid. Int Res J Pharm 2012;3:106-13
6. Hite M, Turner S, Federici C. Part 1: Oral delivery of poorly soluble drugs.
pharmaceutical manufacturing and packing issue. 2003. Drugs pharm manuf packing
source available at: http://www.scolr.com/lit/PMPS_2003_1.pdf [Last accessed 24 March
2013]
7. Mohanachandran PS, Sindhumol PG, Kiran TS. Enhancement of solubility and
dissolution rate: an overview. Int J Comp Pharm 2010;4:1-10
8. Pouton CW. Formulation of poorly water-soluble drugs for oral administration:
physicochemical and physiological issues and the lipid formulation classification system.
EurJPharm Sci 2006;29:278-87
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 52
9. Leuner C, Dressman J. Improving drug solubility for oral delivery using solid dispersions.
EurJPharm Biopharm 2000;50:47-60
10. Sareen S, Mathew G, Joseph L. Improvement in solubility of poor water soluble drugs by
solid dispersion. Int J Pharm Invest 2012;2:12-7
11. Kapoor B, Kaur R, Kour S, et al. Solid dispersion: an evolutionary approach for solubility
enhancement of poorly water soluble drugs. Int JRec Adv Pharm Res 2012;2:1-16
12. Duarte I, Temtem M, Gil M, Gaspar F. Overcoming poor bioavailability through
amorphous solid dispersions. Ind Pharm 2011;30:4-6
13. Vasconcelos T, Sarmento B, Costa P. Solid dispersion as strategy to improve oral
bioavailability of poor water soluble drugs. Drug Discovery Today 2007;12:1068-75
14. Dhirendra K, Lewis S, Udupa N, Atin K. Solid dispersion: a review. Pak J Pharm Sci
2009;22:234-46
15. Calahan JL. Characterization of amorphous solid dispersions of AMG 517 in HPMC-AS
and crystallization using isothermal microcalorimetry. 2011 University of Kansas.
Available online at: http://kuscholarworks.ku.edu/dspace/handle/1808/7647 [Last
accessed 20 April 2013]
16. Baird JA, Taylor LS. Evaluation of amorphous solid dispersion properties using thermal
analysis techniques. Adv Drug Del Rev 2012; 64: 396–421
17. Newman A. Presentation on basics of amorphous and amorphous solid dispersions. 2010.
Seven street development group. Available online at: www.seventhstreetdev.com [Last
accessed 20 Feb 2013]
18. Singh S, Baghel RS, Yadav L. A review on solid dispersion. Int J Pharm Life Sci
2011;2:1078-95
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 53
19. Appel L. Presentation on amorphous solid dispersion. 2009. Green ride consulting.
Available online at: http://www.pharmatek.com/pdf/PTEKU/Jul302009.pdf [Last
accessed 15 January 2013]
20. Arunachalam A, Karthikeyan M, Konam K, et al. Solid dispersion: a review. Central
Pharm Res2010;1:82-90
21. Luhadiya A, Agrawal S, Jain P, Dubey PK. A review on solid dispersion. Int J Adv Res
Pharm BioSci 2012;1:281-91
22. Dai WG, Pollock-dove C, Dong LC, Li S. Advanced screening assays to rapidly identify
solubility-enhancing formulations: high-throughput, miniaturization and automation. Adv
Drug Deliver Rev 2008;60:657-72
23. Ghebremeskel AN, Vemavarapu C, Lodaya M. Use of surfactants as plasticizers in
preparing solid dispersions of poorly soluble drug: selection of polymer–surfactant
combinations using solubility parameters and testing the processability. Int J Pharm
2007;328:119-29
24. Dai WG, Dong LC, Li S, et al. Parallel screening approach to identify solubility-
enhancing formulations for improved bioavailability of a poorly water-soluble compound
using milligram quantities of material. Int J Pharm 2007;336:1-11
25. Shanbhag A, Rabel S, Nauka E, et al. Method for screening of solid dispersion
formulations of low-solubility compounds-miniaturization and automation of solvent
casting and dissolution testing. Int J Pharm 2008;351:209-18
26. Barillaro V, Pescarmona PP, Speybroeck MV, et al. High-throughput study of phenytoin
solid dispersions: formulation using an automated solvent casting method, dissolution
testing, and scaling-up. J Comb Chem 2008;10:637-43
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 54
27. Masky P, Dai WG, Li S, et al. Screening method to identify preclinical liquid and semi-
solid formulations for low solubility compounds: miniaturization and automation of
solvent casting and dissolution testing. J Pharm Sci2007;96:1548-63
28. Arnum PV. Meeting solubility challenges. Pharm Technol2012;1:36-8
29. Paudel A, Worku ZA, Meeus J, et al. Manufacturing of solid dispersions of poorly water
soluble drugs by spray drying: Formulation and process considerations. Int J Pharm 2012
doi: http://dx.doi.org/ 10.1016/j.ijpharm.2012.07.015
30. Patel RP, Patel MP, Suthar AM. Spray drying technology: an overview. Indian J Sci
Technol. 2009;2:44-7
31. Vehring R. Pharmaceutical particle engineering via spray drying. Pharm Res
2008;25:999-1022
32. Vehring R, Foss WR, Lechuga-Ballesteros D. Particle formation in spray drying. Aerosol
Sci 2007;38:728-46
33. Nandiyanto ABD, Okuyama K. Progress in developing spray-drying methods for the
production of controlled morphology particles: from the nanometer to submicrometer size
ranges. Adv Powder Technol 2011;22:1-19
34. Alhnan MA, Kidia E, Basit AW. Spray-drying enteric polymers from aqueous solutions:
a novel, economic, and environmentally friendly approach to produce pH-responsive
microparticles. Eur J Pharm Biopharm 2011;79:432–9
35. Parikh DM. Achieving pharmaceutical solubility enhancements using spray drying.2008
Available online at: http://www.powderbulksolids.com/article/achieving-pharmaceutical-
solubility-enhancements-using-spray-drying [Last accessed 22 July 2013]
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 55
36. Rogers TL, Overhoff KA, Shah P, et al. Micronized powders of a poorly water soluble
drug produced by a spray-freezing into liquid-emulsion process. Eur J Pharm
Biopharm2003;55:161–72
37. Tong HHY, Du Z, Wang GN, et al. Spray freeze drying with polyvinyl pyrrolidone and
sodium caprate for improved dissolution and oral bioavailability of oleanolic acid, a BCS
class IV compound. Int J Pharm 2011;404:148–58
38. Sollohub K, Janczyk M, Kutyla A, et al. Taste masking of roxithromycin by spray drying
technique. Acta Poloniae Pharm - Drug Res 2011;68:601-4
39. Martino PD, Scoppa M, Joiris E, et al. The spray drying of acetazolamide as method to
modify crystal properties and to improve compression behavior. Int J Pharm
2001;213:209–21
40. The influence of the different process parameters on the dependent variables in spray
drying method. Buchi training documents. Available at www.buchi.com [Last accessed
20 December 2012]
41. Huntington DH. The influence of spray drying process on product properties. Drying
Technol 2004;22:1261-87
42. Wu JX, Yang M, Berg FV, et al. Influence of solvent evaporation rate and formulation
factors on solid dispersion physical stability. Eur J Pharm Sci 2011; 44: 610-20
43. Paudel A, Mooter GV. Influence of solvent composition on the miscibility and physical
stability of naproxen/PVP K 25 solid dispersions prepared by cosolvent spray-drying.
Pharm Res 2012;29:251-70
44. ICH Topic Q3C (R5) Impurities: Guideline for residual solvents. European medicines
agency, 2011. March 2011 EMA/CHMP/ICH/82260/2006
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 56
45. ICH Impurities: Guideline for residual solvents Q3C(R5) Current Step 4 version dated 4
February 2011.International Conference on Harmonisation, Geneva.
46. Mahapatra AK, Murthy PN, Rani ER, et al. An updated review on technical advances to
enhance dissolution rate of hydrophobic drugs. Int Res J Pharm 2012;3:1-7
47. Shi D, Loxely A, Lee RW, Fairhurst D. A novel spray drying technology to improve the
bioavailability of BCS class II molecules. Drug Dev Del 2012;12:1-7
48. Hugo M, Kunath K, Dressman J. Selection of excipient, solvent and packaging to
optimize the performance of spray-dried formulations: case example fenofibrate. Drug
DevInd Pharm 2013;39:402-12
49. Behera AL, Sahoo SK, Patil SV. Enhancement of solubility: A pharmaceutical overview.
Der Pharmacia Lettre 2010;2:310-18
50. Jouyban A, SoltanpourSh, Chan HK. A simple relationship between dielectric constant of
mixed solvents with solvent composition and temperature. Int J Pharm 2004;269:353-60
51. Fakhree AA, Delgado DR, Martinez F, Jouyban A. The importance of dielectric constant
for drug solubility prediction in binary solvent mixtures: electrolytes and zwitterions in
water + ethanol. AAPS PharmSciTech 2010;11:1726-29
52. Al-Obaidi H, Ke P, Brocchini S, Buckton G. Characterization and stability of ternary
solid dispersions with PVP and PHPMA. Int J Pharm 2011;419:20-7
53. Esposito E, Roncarati R, Cortesi R, et al. Production of EUDRAGIT® microparticles by
spray-drying technique: Influence of experimental parameters on morphological and
dimensional characteristics. Pharm Dev Technol 2000;5:267-78
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 57
54. Rattes ALR, Oliveira WP. Spray drying conditions and encapsulating composition effects
on formation and properties of sodium diclofenac microparticles. Powder Technol
2007;171:7-14
55. Harjunen P, Lehto VP, Vallisari J, et al. Effects of ethanol to water ratio in feed solution
on the crystallinity of spray-dried lactose. Drug Dev Ind Pharm 2002;28:949-55
56. Bittner B, Kissel T. Ultrasonic atomization for spray drying: a versatile technique for the
preparation of protein loaded biodegradable microspheres. J Microencapsulation
1999;16:325-41
57. Cal K, Sollohub K. Spray drying technique I: Hardware and process parameters. J Pharm
Res 2010; 99:575-86
58. Types of atomizer used in pharmaceutical spray drying. Available at:
http://www.niroinc.com/technologies/atomizers.asp [Last accessed 20 December 2012]
59. Mizoe T, Beppu S, Ozeki T, Okada H. One-step preparation of drug-containing
microparticles to enhance the dissolution and absorption of poorly water-soluble drugs
using a 4-fluid nozzle spray drier. J control Release 2007;120:205-10
60. Chen R, Okamoto H, Danjo K. Preparation of functional composite particles of
salbutamol sulfate using a 4-fluid nozzle spray-drying technique. Chem Pharm Bull
2008;56:254-9
61. Lastow O, Andersson J, Nilsson A, Balachandran W. Low-voltage electrohydrodynamic
(EHD) spray drying of respirable particles. Pharm DevTechnol 2007;12:175-81
62. Kuang LL, Chi-Hwa W, Smith KA. On the fabrication of microparticles using
electrohydrodynamic atomization method. Available online at:
dspace.mit.edu/bitstream/handle/1721.1/7480/MEBCS009.pdf
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 58
63. T Ciach. Application of electro-hydro-dynamic atomization in drug delivery. J Drug Del
Sci Tech 2007;17: 367-75
64. Yurteri CU, Hartman RPA, Marijniseen JCM. Producing pharmaceutical particles via
electrospraying with an emphasis on nano and nano structured particles - A Review.
KONA Powder and Particle J 2010;28:91-115
65. Alexander K, King C.Factors governing surface morphology of spray-dried amorphous
substances. Drying Technol1985;3:321–48
66. Littringer EM., Mescher A., Eckhard S, et al. Spray drying of mannitol as a drug
carrier—the impact of process parameters on product properties. Drying Technol
2012;30:114–24
67. Maury M, Murphy K, Kumar S, et al. Effects of process variables on the powder yield of
spray-dried trehalose on a laboratory spray dryer. Eur J Pharm Biopharm2005;59:565–73
68. Mass SG, Schaldach G, Littringer EM, et al. The impact of spray drying outlet
temperature on the particle morphology of mannitol. Powder Technol 2011;213:27-35
69. Paramita V, Iida K, Yoshii H, Furuta T. Effect of additives on the morphology of spray-
dried powder. Dry Technol 2010;28:323-9
70. Mahdjoub H, Roy P, Filiatre C, et al. The effect of the slurry formulation upon the
morphology of spray-dried yia stabilised zirconia particles. J Eur Ceram Soc
2003;23:1637-48
71. Aejaz A, Jafar M, Dehghan M, Shareef A. Meloxicam-PVP-SLS ternary solid dispersion
system: in vitro and in vivo evaluation. Int J Pharm & Pharm Sci 2010;2:182-90
72. Shinde VR, Pore YV, Rao JV. Development and characterization of ternary solid
dispersion systems of olmesartan medoxomil. Latin American J Pharm 2011;30:2011-5
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 59
73. Janseens S, Nagels S, Armas HN, et al. Formulation and characterization of ternary solid
dispersions made up of Itraconazole and 2 excipients, TPGS 1000 and PVPVA 64, that
were selected based on a supersaturation screening study. Eur J Pharm Biopharm
Accepted on 12 November 2007 doi:10.1016/j.ejpb.2007.11.004.
74. Maghraby GME, Alomrani A. Effect of binary and ternary solid dispersion on the in vitro
dissolution and in-situ rabbit intestinal absorption of gliclazide. Pakistan J Pharm Sci
2011;24:459-68
75. Rahmati MR, Vetanara A, Parsian AR, et al. Effect of formulation ingredients on the
physical characteristics of salmeterolxinafoate microparticles tailored by spray freeze
drying. Adv Powder Technol 2013;24:36-42
76. SIPERNAT®
speciality silica and AERSOIL® fumed silica in spray drying application.
Evonikspeciality product technical information. Available from www.evonik.com,
www.aerosil.com and www.sipernat.com [Last accessed: 13 December 2012]
77. Mahajan HS, Girnar GA, Nerkar P. Dissolution and bioavailability enhancement of
gliclazide by surface solid dispersion using spray drying technique. Indian J Novel Drug
Del 2012;4:115-24
78. Planinsek O, Kovacic B, Vrecer F. Carvedilol dissolution improvement by preparation of
solid dispersions with porous silica. Int J Pharm 2011;406:41-8
79. Pokharkar VB, Mandpe LP, Padamwar MN, et al. Development, characterization and
stabilization of amorphous form of a low Tg drug. Powder Technol 2006;167:20-5
80. Ambike AA, Mahadik KR, Paradkar A. Spray-dried amorphous solid dispersions of
simvastatin, a low Tg drug: in vitro and in vivo evaluations. Pharm Res 2005;22:990-8
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 60
81. Chauhan B, Shimpi S, Paradkar A. Preparation and evaluation of glibenclamide-
polyglycolized glycerides solid dispersions with silicon dioxide by spray drying
technique. Eur J Pharm Sci 2005;26:219-30
82. Martins RM, Pereira SV, Machado MO, et al. Preparation of microparticles of
hydrochlorthiazide by spray drying. 2011. European Drying Conference – Euro Drying
83. Takeuchi H, Nagira S, Yamamoto H, Kawashima Y. Solid dispersion particles of
amorphous indomethacin with fine porous silica particles by using spray-drying method.
Int J Pharm 2005;293:155-64
84. Shen SC, Ng WK, Chia L, et al. Physical state and dissolution of ibuprofen formulated by
co-spray drying with mesoporous silica: effect of pore and particle size. Int J Pharm
2011;410:188-95
85. Makai Z, Bajdik J, Eros I, Hodi KP. Evaluation of the effects of lactose on the surface
properties of alginate coated trandolapril particles prepared by a spray-drying method.
Carbohydr Polym 2008;74:712-16
86. Yu Lian. Amorphous pharmaceutical solids: preparation, characterization and
stabilization. Adv Drug DeliverRev 2001;48:27-42
87. Laitinen R, Lobmann K, Strachan CJ, et al. Emerging trends in the stabilization of
amorphous drugs. Int J Pharm Available online 28 April 2012. doi:
http://dx.doi.org/10.1016/j.ijpharm.2012.04.066
88. Beck C, Sieven L, Gartner K, et al. Effects of stabilizers on particle redispersion and
dissolution from polymer strip films containing liquid antisolvent precipitated
griseofulvin particles. Powder Technol2013;236:37-51
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 61
89. Gil M, Vicente J, Gaspar F. Scale-up methodology for pharmaceutical spray drying.
ChemToday 2010;28:18-22
90. Dobry DE, Settell DM, Baumann JA, et al. A model-based methodology for spray drying
process development. J Pharm Innov 2009;4:133-142
91. Thybo P, Hovgaard L, Lindelov JS, et al. Scaling up the spray drying process from pilot
to production scale using an atomized droplet size criterion. Pharm Res 2008;25:1610-20
92. Bloom CJ. Presentation on spray-dried dispersions: robust formulation and science of
scale from preclinical to launch. Bend research. Available online at:
http://www.bendresearch.com[Last accessed 29March 2013].
93. Arpagaus C, Schwatzbach H. Scale-up from bench-top research to laboratory production.
Buchi technical bulletin. 2008. Available at: www.buchi.com [Last accessed 27
November 2012]
94. Schwatzbach H. The possibilities and challenges of spray drying. PharmTechnol Europe.
2010;22:5-8
95. Paradkar A, Ambike AA, Jadhav BK, Mahadik KR. Characterization of curcumin–PVP
solid dispersionobtained by spray drying. Int J Pharm 2004;271:281–6
96. Crowley KJ, Zografi G. Water vapor absorption into amorphous hydrophobic
drug/poly(vinylpyrrolidone) dispersions. J Pharm Sci 2002;91:2150–65
97. Kanno H, Taylor LS. Influence of different polymers on the crystallization tendency of
molecularly dispersed amorphous felodipine. J Pharm Sci2006;95:2692-705
98. Bhinse SD. Ternary Solid Dispersions of Fenofibrate with Poloxamer 188 and TPGS for
Enhancement of Solubility And Bioavailability. Int J Res Pharm Biomed Sci 2011;2:583-
95
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 62
99. Stephen Collins. Differential scanning calorimetry. Available at:
http://www.dur.ac.uk/n.r.cameron/Assets/Grouptalks/DSCpresentation.ppt [Last accessed
12 December 2012]
100. Sichina WJ. Measurement of Tg by DSC. Thermal Analysis application note. Available
at: www.perkinelmer.com [Last accessed 12 January 2012]
101. Differential scanning calorimetry: A bulk analytical technique. Available online at:
http://www4.ncsu.edu/mwg-internal/de5fs23hu73ds/progress?id=0LSk/uj9mM [Last
accessed: 6 January 2013]
102. Paul Gabbott. Chapter 1: A practical introduction to differential scanning calorimetry.
2008. Doi: 10.1002/9780470697702.ch1. Blackwell Publishing Ltd.
103. Interpreting DSC curves Part I: Dynamic measurements. Information for user of Mettler
Toledo thermal analysis systems. 2000. Available online at:
http://www.masontechnology.ie/x/Usercom_11.pdf [Last accessed 4 January 2013]
104. Lebrun P, Krier F, Mantanus J, Grohganz H, Yang M, Rozet E, Boulanger B, Evrard B,
Rantanen J, Hubert P. Design space approach in the optimization of the spray-drying
process. Eur J Pharm Biopharm 2012;80:226-34
105. International Conference on Harmonization of technical requirements for registration of
pharmaceuticals for human use. Pharmaceutical development ICH Q8 (R2). August 2009
106. Yu LX, Lionberger RA, Raw AS, D’ Costa R, Wu H, Hussain AS. Applications of
process analytical technology to crystallization processes. Adv Drug Deliver Rev
2004;56:349-69
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 63
107. Amaro MI, Tajber L, Corrigan OI, Healy AM, Optimisation of spray drying process
conditions for sugar nanoporous microparticles (Npmps) intended for inhalation, Int J
Pharm 2011;421:99-109
108. Technical data Büchi B-290, available at: www.buchi.com, Drying, Mini spray dryer B-
290. Last accessed June 20, 2013.
109. Baldinger A, Clerdent L, Rantanen J, Yang M, Grohganz H. Quality by design approach
in the optimization of the spray-drying process. Pharm Dev Technol 2012;17:389-97
110. Prinn KB, Constantino HR, Tracy M. Statistical modelling of protein spray drying at the
lab scale. AAPS PharmSciTech 2002;3: E4
111. Maltesen, MJ, Bjerregaard, S, Hovgaard L, Havelund S, van de Weert M. Quality by
design – Spray drying of insulin intended for inhalation. Eur J Pharm Biopharm
2008;70:828-38
112. Stahl K, Claesson M, Lilliehorn P, Linden H, Backstrom K. The effect of process
variables on the degradation and physical properties of spray dried insulin intended for
inhalation. Int J Pharm 2002;233:227-37
113. Maury M, Murphy K, Sandeep K, Shi L, Lee G. Effects of process variables on the
powder yield of spray-dried trehalose on a laboratory spray-dryer. Eur J Pharm Biopharm
2005;59:565–73
114. Al-Asheh S, Jumah R, Banat F, Hammad S. The use of experimental factorial design for
analysing the effect of spray dryer operating variables on the production of tomato
powder. Food Bioprod 2003;part C:81-88
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 64
115. Tajber L, Corrigan OI, Healy AM. Spray drying of budesonide, formoterol fumarate and
their composites – II. Statistical factorial design and in vitro deposition properties. Int J
Pharm 2009;367:86-96
116. Healy AM, McDonald BF, Tajber L, Corrigan OI. Characterisation of excipient-free
nanoporous microparticles (NPMPs) of bendroflumethiazide. Eur J Pharm Biopharm
2008;69:1182 –86
117. Papelis C, Um W, Russel CE, Chapman JB. Measuring the specific surface area of natural
and manmade glasses: effects of formation process, morphology, and particle size.
Colloids Surf A: Physicochem Eng Aspects 2003;215:221-39
118. Cabral-Marques H, Almeida R. Optimisation of spray-drying process variables for dry
powder inhalation (DPI) formulations of corticosteroid/cyclodextrin inclusion complexes.
Eur J Pharm Biopharm 2009;73:121-29
119. Poddar SS, Nigade SU, Singh DK. Designing of ritonavir solid dispersion through spray
drying. Der Pharmacia lett 2011;3:213-23
120. Patel TB, Patel LD, Patel TB, et al. Enhancement of dissolution rate and oral absorption
of drug insoluble in gastric fluid by spray dried microparticles. Int J Chem Tech Res
2010;2:185-93
121. Muttil P, Kaur J, Kumar K, et al. Inhalable microparticles containing large payload of
antituberculosis drugs. Eur J Pharm Sci 2007;32:140-50
122. Naikwade SR, Bajaj AN, Gurav P, et al. Development of budesonide microparticles using
spray-drying technology for pulmonary administration: design, characterization, in vitro
evaluation, and in vivo efficacy study. AAPS PharmScitech2009;10:993-1012
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 65
123. Pilcer G, Vanderbist F, Amighi K. Preparation and characterization of spray-dried
tobramycin powders containing nanoparticles for pulmonary delivery. Int J Pharm
2009;365:162-9
124. Jafarinejad S, Gilani K, Moazeni E, et al. Development of chitosan-based nanoparticles
for pulmonary delivery of Itraconazole as dry powder formulation. Powder Technol
2012;222:65-70
125. Cook RO, Pannu RK, Kellaway IW. Novel sustained release microspheres for pulmonary
drug delivery. J Control Release 2005;104:79-90
126. Cruz L, Fattal E, Tasso L, et al. Formulation and in vivo evaluation of sodium alendronate
spray-dried microparticles intended for lung delivery. J Control Release 2011;152:370-5
127. Al-Qadi S, Grenha A, Recio DC, et al. Microencapsulated chitosan nanoparticles for
pulmonary protein delivery: In vivo evaluation of insulin-loaded formulations. J Control
Release 2012;157:383-90
128. Beck-Broichsitter M, Schweiger C, Schmehl T, et al. Characterization of novel spray-
dried polymeric particles for controlled pulmonary drug delivery. J Control Release
2012;158:329-35
129. Sham J, Zhang Y, Finlay WH, et at. Formulation and characterization of spray-dried
powders containing nanoparticles for aerosol delivery to the lung. Int J Pharm
2004;269:457-67
130. Steckel H, Brandes HG. A novel spray-drying technique to produce low density particles
for pulmonary delivery. Int J Pharm 2004;278:187-95
131. Klinger C, Muller BW, Steckel H. Insulin-micro and nanoparticles for pulmonary
delivery. Int J Pharm 2009;377:173-9
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 66
132. Burki K, Jeon I, Arpagaus C, Getz G. New insights into respirable protein powder
preparation using a nano spray dryer. Int J Pharm 2011;408:248-56
133. Nolan LM, Tajber L, McDonald BF, et al. Excipient-free nanoporous microparticles of
budesonide for pulmonary delivery. Eur J Pharm Sci 2009;37:593-602
134. Li HY, Song X, Seville PC. The use of sodium carboxy methylcellulose in the
preparation of spray-dried proteins for pulmonary drug delivery. Eur J Pharm Sci
2010;40:56-61
135. Adi H, Young PM, Chan HK, et al. Co-spray-dried mannitol–ciprofloxacin dry powder
inhaler formulation for cystic fibrosis and chronic obstructive pulmonary disease. Eur J
Pharm Biopharm 2010;40:239-47
136. Imgartinger M, Cmuglia V, Damm M, et al. Pulmonary delivery of therapeutic peptides
via dry powder inhalation: effects of micronisation and manufacturing. Eur J Pharm
Biopharm 2004;58:7-14
137. Schule S, Fedemrecht S, Garidel P, et al. Stabilization of IgG1 in spray-dried powders for
inhalation. Eur J Pharm Biopharm 2008;69:793-807
138. Thi TH, Danede F, Descamps M, Flament M. Comparison of physical and inhalation
properties of spray-dried and micronized terbutaline sulphate. Eur J Pharm Biopharm
2008;70:380-8
139. Sansone F, Aquino RP, Gaudio D, et al. Physical characteristics and aerosol performance
of naringin dry powders for pulmonary delivery prepared by spray-drying. Eur J Pharm
Biopharm 2009;72:206-13
140. Sou T, Meeusen EN, Veer M, et al. New developments in dry powder pulmonary vaccine
delivery. Trends Biotechnol 2011;29:191-8
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 67
141. Grenha A, Ramunan C, Edison LS, Seijo B. Microspheres containing lipid/chitosan
nanoparticles complexes for pulmonary delivery of therapeutic proteins. Eur J Pharm
Biopharm 2008;69:83-93
142. Hascicek C, Gonul N, Erk N. Mucoadhesive microspheres containing gentamicin sulfate
for nasal administration: preparation and in vitro characterization. II Farmaco
2003;58:11-6
143. Coucke D, Schotsaert M, Libert C, et al. Spray-dried powders of starch and crosslinked
poly (acrylic acid) as carriers for nasal delivery of inactivated influenza vaccine. Vaccine
2009;27:1279-86
144. Mahajan HS, Tatiya BV, Nerkar PP. Ondansetron loaded pectin based microspheres for
nasal administration: In vitro and in vivo studies. Powder Technol 2012;221:168-76
145. Kaye RS, Paurewal TS, Alpar OH. Development and testing of particulate formulations
for the nasal delivery of antibodies. J Control Release 2009;135:127-35
146. Alhalaweh A, Andersson S, Velaga SP. Preparation of zolmitriptan–chitosan
microparticles by spray drying for nasal delivery. Eur J Pharm Sci 2009;38:206-14
147. Gavini E, Rassu G, Muzzarelli C, et al. Spray-dried microspheres based on methyl
pyrrolidinone chitosan as new carrier for nasal administration of metoclopramide. Eur J
Pharm Biopharm 2008;68:245-52
148. Kim JS, Kim MS, Park HJ, et al. Physicochemical properties and oral bioavailability of
amorphous Atorvastatin hemi-calcium using spray-drying and SAS process. Int J Pharm
2008;359:211-9
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 68
149. Hu J, Ng WK, Dong Y, et al. Continuous and scalable process for water-redispersible
nanoformulation of poorly aqueous soluble drugs by antisolvent precipitation and spray-
drying. Int J Pharm 2011;404:198-204
150. Stulzer HK, Tagliari MP, Parize AL, et al. Evaluation of cross-linked chitosan
microparticles containing acyclovir obtained by spray-drying. Mat Sci Engineering
2009;29:87-92
151. Alanazi FK, El-Badry M, Ahmed MO, Alsarra A. Improvement of albendazole
dissolution by preparing microparticles using spray-drying technique. Scientia
Pharmaceutica 2007;75:63-79
152. Bhise SD. Ternary solid dispersions of fenofibrate with poloxamer 188 and TPGS for
enhancement of solubility and bioavailability. Int J Res Pharm Biomed Sci 2011;2:583-95
153. Elkordy AA, Essa EA. Dissolution of ibuprofen from spray dried and spray chilled
particles. Pakistan J Pharm Sci 2010;23:284-90
154. Shah SS, Pasha TY, Behera AK, et al. Solubility enhancement and physicochemical
characterization of inclusion complexes of Itraconazole. Der Pharmacia Lett 2012;4:354-
66
155. Shu B, Yu W, Zhao Y, et al. Study on microencapsulation of lycopene by spray-drying. J
Food Eng 2006; 76: 664-9
156. Schafroth N, Arpagaus C, Jadhav UY, et al. Nano and microparticle engineering of water
insoluble drugs using a novel spray-drying process. Colloids Surf B: Biointerf 2012;90:8-
15
157. Kolakovic R, Laaksonen T, Peltonen L, et al. Spray-dried nanofibrillar cellulose
microparticles for sustained drug release. Int J Pharm 2012;430:47-55
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 69
158. Dixit M, Kini AG, Kulkarni PK. Preparation and characterization of microparticles of
piroxicam by spray drying and spray chilling methods. Res Pharm Sci 2010;5:89-97
159. Lee SH, Heng D, Ng W, et al. Nano spray drying: A novel method for preparing protein
nanoparticles for protein therapy. Int J Pharm 2011;403:192-200
160. Gedam SS and Tapar KK. Taste masking and characterization of Diphynehydramine
hydrochloride by spray drying. Int J Pharm Res Dev 2010;1:1-7
161. Kristmundsdottir T, Gudmundsson OS, Ingvarsdottir K. Release of diltiazem from
EUDRAGIT®
microparticles prepared by spray drying. Int J Pharm 1996;137:159-65
162. Jung JY, Yoo SD, Lee SH, et al. Enhanced solubility and dissolution rate of itraconazole
by a solid dispersion technique. Int J Pharm 1999;187:209-18
163. Weuts I, Kempen D, Verreck G, et al. Study of the physicochemical properties and
stability of solid dispersions of loperamide and PEG 6000 prepared by spray drying. Eur J
Pharm Biopharm 2005;59:119-26
164. Joe JH, Lee WM, Park Y, et al. Effect of the solid-dispersion method on the solubility and
crystalline property of tacrolimus. Int J Pharm 2010;395:161-6
165. Yoshida T, Kurimoto I, Yoshihara K, et al. Aminoalkyl methacrylate copolymers for
improving the solubility of tacrolimus I. Int J Pharm 2012;428:18-24
166. Uchiyama H, Tozuka Y, Imono M, et al. Improvement of dissolution and absorption
properties of poorly water-soluble drug by preparing spray-dried powders with α-glucosyl
hesperidin. Int J Pharm 2010;392:101-6
167. Sansone F, Picerno P, Mencherini T, et al. Flavonoid microparticles by spray-drying:
Influence of enhancers of the dissolution rate on properties and stability. J Food Eng
2011;103:188-96
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 70
168. Li C, Li C, Le Y, Chen JF. Formation of bicalutamide nanodispersion for dissolution rate
enhancement. Int J Pharm 2011;404:257-63
169. Zhang Z, Le Y, Wang J, et al. Irbesartan drug formulated as nanocomposite particles for
the enhancement of the dissolution rate. Particuology. 2012;10:462-67
170. Al-Zoubi N, Alkhatib HS, Bustanji Y, et al. Sustained-release of buspirone HCl by co
spray-drying with aqueous polymeric dispersions. Eur J Pharm Biopharm 2008;69:735-42
171. Pawar R, Shinde SV, Deshmukh S. Solubility enhancement of pioglitazone by spray
drying techniques using hydrophilic carriers. J Pharm Res 2012;5:2500-4
172. Biradar SV, Patil AR, Sudarsan GV, et al. A comparative study of approaches used to
improve solubility of roxithromycin. Powder Technol 2006;169:22-32
173. Ambike AA, Mahadik KR, Paradkar A. Stability study of amorphous valdecoxib. Int J
Pharm 2004;282:151-62
174. Quaglia F, Rosa GD, Granata E, et al. F eeding liquid, non-ionic surfactant and
cyclodextrin affect the properties of insulin-loaded poly (lactide-co-glycolide)
microspheres prepared by spray-drying. J Control Release 2003;86:267-78
175. Jensen DMK, Cun D, Maltesen M, et al. Spray drying of siRNA-containing PLGA
nanoparticles intended for inhalation. J Control Release 2010;142:138-45
176. Gavini E, Chetoni P, Cossu M, et al. PLGA microspheres for the ocular delivery of a
peptide drug, vancomycin using emulsification/spray-drying as the preparation method: in
vitro/in vivo studies. Eur J Pharm Biopharm 2004;57:207-12
177. Badee AZM, Amal E, Kader AE, Aly HM. Microencapsulation of peppermint oil by
spray drying. Aust J Basic and App Sci 2012;6:499-504
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 71
178. Cai YZ, Corke H. Production and properties of spray dried Amaranthus betacyanin
pigments. J Food Sci 2000;65:1248-52
179. Soottitantawa A, Tkayama K, Okamura K, et al. Microencapsulation of l-menthol by
spray drying and its release characteristics. Innov Food Sci Emerging Technol
2005;6:163-70
180. Turchiuli C, Fuchs M, Bohin M, et al. Oil encapsulation by spray drying and fluidized
bed agglomeration. Innov Food Sci Emerging Technol 2005;6:29-35
181. Gallardo G, Guida L, Martinez V, et al. Microencaspulation of linseed oil by spray drying
for functional food application. Food Res App 2013;52:473-482
182. Fang Z, Bhandari B. Comparing the efficacy of protein and maltodextrin on spray drying
of bayberry juice. Food Res Int 2012;48:478-83
183. Osorio C, Forero DP, Carriazo JG. Characterization and performance assessment of
guava (Psidium guajava L.) microencapsulates obtained by spray-drying. Food Res Int
2011;44:1174-81
184. Borrmann D, Pierucci APT, Ferreira SG, et al. Microencapsulation of passion fruit
(Passiflora) juice with n-octenylsuccinate-derivatised starch using spray-drying. Food
Bio Process 2013;91:23-7
185. Fu N, Zhou Z, Jones TB et al. Production of monodisperse epigallocatechin gallate
(EGCG) microparticles by spray drying for high antioxidant activity retention. Int J
Pharm 2011;413:155-66
186. Obon JM, Castellar MR, Alacid M, et al. Production of a red–purple food colorant from
Opuntia stricta fruits by spray drying and its application in food model systems. J Food
Eng 2009;90:471-9
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 72
187. Shu B, Yu W, Zhao Y, et al. Study on microencapsulation of lycopene by spray-drying. J
Food Eng 2006;76:664-9
188. Bayram OA, Bayram M, Tekin AR. Spray drying of sumac flavour using sodium
chloride, sucrose, glucose and starch as carriers. J Food Eng 2005;69:253-60
189. Luna-Solano G, Salgado-Carvantes MA, Jimenes R, et al. Optimization of brewer’s yeast
by spray drying process. J Food Eng 2005;68:9-18
190. Goula AM, Adamopoulos KG. Spray drying of tomato pulp in dehumidified air. J Food
Eng 2005;66:25-34
191. Laohasongkram K, Mahamaktudsanee T, Chaiwanichsiri S, Microencapsulation of
macadamia oil by spray drying. Procedia Food Sci 2011;1:1660-5
192. Anwar SH, Kunz B. The influence of drying methods on the stabilization of fish oil
microcapsules: Comparison of spray granulation, spray drying, and freeze drying. J Food
Eng 2011;105:367-78
193. Jinapong N, Suphantharika M, Jamnong P. Production of instant soymilk powders by
ultrafiltration, spray drying and fluidized bed agglomeration. J Food Eng 2008;84:194-
205
194. Ohtake S, Martin RA, Yee L, et al. Heat-stable measles vaccine produced by spray
drying. Vaccine 2010;28:1275-84
195. Saluja V, Amorij JP, Kapteyn JC, et al. A comparison between spray drying and spray
freeze drying to produce an influenza subunit vaccine powder for inhalation. J Control
Release 2010;144:127-33
196. Fritzen-Freire CB, Prudencio ES, Amboni RD, et al. Microencapsulation of bifidobacteria
by spray drying in the presence of prebiotics. Food Res Int 2012;45:306-12
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 73
2.2 Polymer review
2.2.1 EUDRAGIT® E PO
Chemical/IUPAC Name Poly (butylmethacylate-co-(2-dimethylaminoethyl)
methacrylate-co-methyl methacrylate) 1:2:1
INCI name Acrylates / Dimethylaminoethyl methacrylate copolymer
Physical properties EUDRAGIT®
E PO is a solid substance in form of white powder
with a characteristic amine like odor.
Molar mass MW approx. 47,000 g/mol
In previous publication the approximately weight average molar mass was indicated to be
150,000. This was determined by viscometry in the 1960ies and has never been
reevaluated since then. The determination of the molecular mass distribution of acrylic
copolymer by size exclusion chromatography (SEC) or gel permeation chromatography
(GPC), respectively, is difficult due to adsorptive and associative phenomena of these
polymers. In 2004 a robust SEC method for the determination of molar mass distribution
was developed for this polymer. Based on this method the weight average molar mass is
approximately MW 47,000 g/mol.
Chemical properties EUDRAGIT® E PO is a cationic copolymer based on
dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate.
Solid substance obtained from EUDRAGIT® E 100 by micronization.
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 74
Figure 2.7 Chemical structure of EUDRAGIT®
E PO
The monomers are statistically ordered in the copolymer chain.
Regulatory Compliance EUDRAGIT®
E PO meets the specifications of following
pharmacopoeias:
Ph. Eur. Basic butylated methacrylate copolymer
USP/NF polymer conforms to amino methacrylate copolymer - NF
JPE Aminoalkyl methacrylate copolymer E
Drug Master File EUDRAGIT®
E PO is described in USA drug master file: # 1242
Functional Category Film former; tablet binder; tablet diluent.
Applications in pharmaceutical formulation EUDRAGIT®
E PO is used as a plain or
insulating film former; it is soluble in gastric fluid below pH 5. It is insoluble at above pH
5.
Description EUDRAGIT®
E PO is cationic polymer based on dimethylaminoethyl
methacrylate and other neutral methacrylic acid esters. It is soluble in gastric fluid as well
as in weakly acidic buffer solutions (up to pH < 5). EUDRAGIT®
E PO is available as a
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 75
12.5% ready-to-use solution in propan-2-ol–acetone (60:40). It is light yellow in color
with the characteristic odor of the solvents. EUDRAGIT® E PO is a white free-flowing
powder with at least 95% of dry polymer.
Incompatibilities Incompatibilities occur with certain poly(meth)acrylates dispersions
depending upon the ionic and physical properties of the polymer and solvent. For
example, coagulation may be caused by soluble electrolytes, pH changes, some organic
solvents, and extremes of temperature.
Characteristics of EUDRAGIT® E PO EUDRAGIT
® E PO is a weak acid cation
exchanger polymer with a cross linked polyacrylic backbone. It finds major application in
the taste masking of drugs. It is same as Indion 234 but the particle size distribution is
≤0.075 mm. The characteristics of EUDRAGIT® E PO shown below:
Table 2.12 Characteristics of EUDRAGIT® E PO
Type Weak acid cation exchange Polymer
Appearance White to off white free flowing powder, free from foreign matter
Applications Taste masking of bitter drugs, tablet disintegrants
Matrix type Cross linked polyacrylic
Functional group -COOH-
Particle size range ≤0.075 mm
% Moisture ≤ 10 (10.0 max)
Stability and storage conditions Dry powder polymer forms are stable at temperatures
less than 30°C. Above this temperature, powders tend to form clumps, although this does
not affect the quality of the substance and the clumps can be readily broken up. Dry
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 76
powders are stable for at least 3 years if stored in a tightly closed container at less than
30°C.
Safety Poly(meth)acrylates are widely used as film-coating materials in oral
pharmaceutical formulations. They are also used in topical formulations and are generally
regarded as nontoxic and nonirritant materials. Based on relevant chronic oral toxicity
studies in rats and conventionally calculated with a safety factor of 100, a daily intake of
2–200 mg/kg body-weight depending on the grade of EUDRAGIT® may be regarded as
essentially safe in humans.
Handling Precautions Observe normal precautions appropriate to the circumstances and
quantity of material handled. Additional measures should be taken when handling organic
solutions of poly(meth)acrylates. Eye protection, gloves, and a dust mask or respirator are
recommended. Poly(meth)acrylates should be handled in a well-ventilated environment
and measures should be taken to prevent dust formation.
2.2.2 EUDRAGIT® L 100
CAS number 25086-15-1
FDA UNII 74G4R6TH13
Chemical/IUPAC name Poly(methacylic acid-co-methyl methacrylate) 1:1
INCI name Acrylates copolymer
Physical properties EUDRAGIT® L 100 is a solid substance in form of a white powder
with a faint characteristic odour.
Molar mass information MW approx. 125,000 g/mol
In previous publication the approximately weight average molar mass was indicated to be
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 77
135,000. This was determined by viscometry in the 1960ies and has never been
reevaluated since then. The determination of the molecular mass distribution of acrylic
copolymer by size exclusion chromatography (SEC) or gel permeation chromatography
(GPC), respectively, is difficult due to adsorptive and associative phenomena of these
polymers. In 2004 a robust SEC method for the determination of molar mass distribution
was developed for this polymer. Based on this method the weight average molar mass is
approximately MW 125,000 g/mol.
Chemical properties EUDRAGIT®
L 100 contains an anionic copolymer based on
methacrylic acid and methyl methacrylate. The ratio of the free carboxyl groups to the
ester groups is approx. 1:1. The product contains 0.3 % sodium laurylsulfate Ph. Eur. / NF
on solid substance.
Figure 2.8 Chemical structure of EUDRAGIT®
L 100
The monomers are statistically ordered in the copolymer chain.
Production process Emulsion polymerization and subsequent spray drying
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 78
Compendial Compliance EUDRAGIT® L 100 meets the specifications of following
pharmacopoeias:
Ph. Eur. Methacrylic acid - methyl methacrylate copolymer (1:1)
USP/NF Methacrylic acid copolymer, Type A - NF
JPE Methacrylic acid copolymer L
Drug Master File EUDRAGIT® L 100 is described in USA Drug Master File: # 1242
2.2.3 EUDRAGIT® RL PO
CAS number 33434-24-1
FDA UNII 8GQS4E66YY
Chemical/IUPAC name Poly(ethyl acrylate-co-methyl methacrylate-co-
trimethylammonioethyl methacrylate chloride) 1:2:0.2
INCI name Acrylates / ammonium methacrylate copolymer
Physical properties Solid substance in form of white powder with a faint amine-like
odour.
Molar mass information MW approx. 32,000 g/mol
In previous publication the approximately weight average molar mass was indicated to be
150,000. This was determined by viscometry in the 1960ies and has never been
reevaluated since then. The determination of the molecular mass distribution of acrylic
copolymer by size exclusion chromatography (SEC) or gel permeation chromatography
(GPC), respectively, is difficult due to adsorptive and associative phenomena of these
polymers. In 2004 a robust SEC method for the determination of molar mass distribution
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 79
was developed for this polymer. Based on this method the weight average molar mass is
approximately MW 32,000 g/mol.
Chemical properties EUDRAGIT®
RL PO is a copolymer of ethyl acrylate, methyl
methacrylate and a low content of a methacrylic acid ester with quaternary ammonium
groups (trimethylammonioethyl methacrylate chloride). The ammonium groups are
present as salts and make the polymers permeable.
Solid substance obtained from EUDRAGIT®
RL 100 by milling.
Figure 2.9 Chemical structure of EUDRAGIT®
RL PO
The monomers are statistically ordered in the copolymer chain.
Production process Bulk polymerization, extrusion and subsequent milling
Compendial Compliance EUDRAGIT®
RL PO meets the specifications of following
pharmacopoeias:
Ph. Eur. Ammonio methacrylate copolymer, Type A
USP/NF Ammonio methacrylate copolymer, Type A - NF
JPE Aminoalkyl methacrylate copolymer RS
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 80
2.3 Nifedipine
Description Nifedipine is a drug belonging to a class of pharmacological agents known
as the calcium channel blockers. Nifedipine is 3,5-pyridinedicarboxylic acid, 1,4-dihydro-
2,6-dimethyl-4- (2-nitrophenyl)-, dimethyl ester, C17H18N2O6, and has the structural
formula:
Figure 2.10 Chemical structure of nifedipine
Physical description
Appearance Yellow powder
Melting point 172-174°C
Molecular formula C17H18N2O
Molecular weight 346.3
Solubility and solution stability
It is practically insoluble in water, sparingly soluble in ethanol and freely soluble in
acetone, methylene chloride and chloroform.
Nifedipine solutions are unstable and extremely photosensitive. Decomposition
parameters of photo degradation have been reported. The compound is converted to a
nitrosophenylpyridine derivative when exposed to daylight or certain wavelengths of
artificial light; exposure to UV light may lead to the formation of a nitrophenylpyridine
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 81
derivative. Solutions should be prepared immediately before use in the dark or under light
of wavelength greater than 420 nm.
Clinical pharmacology
Nifedipine is a calcium ion influx inhibitor (slow-channel blocker or calcium ion
antagonist) and inhibits the transmembrane influx of calcium ions into cardiac muscle and
smooth muscle. The contractile processes of cardiac muscle and vascular smooth muscle
are dependent upon the movement of extracellular calcium ions into these cells through
specific ion channels. Nifedipine selectively inhibits calcium ion influx across the cell
membrane of cardiac muscle and vascular smooth muscle without altering serum calcium
concentrations.
Mechanism of action
A) Angina
The precise mechanism by which inhibition of calcium influx relieves angina has not
been fully determined, but includes at least the following 2 mechanisms:
1) Relaxation and prevention of coronary artery spasm
Nifedipine dilates the main coronary arteries and coronary arterioles, both in normal and
ischemic regions, and is a potent inhibitor of coronary artery spasm, whether spontaneous
or ergonovine-induced. This property increases myocardial oxygen delivery in patients
with coronary artery spasm, and is responsible for the effectiveness of nifedipine in
vasospastic (Prinzmetal’s or variant) angina. Whether this effect plays any role in
classical angina is not clear, but studies of exercise tolerance have not shown an increase
in the maximum exercise rate-pressure product, a widely accepted measure of oxygen
utilization. This suggests that, in general, relief of spasm or dilation of coronary arteries is
not an important factor in classical angina.
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 82
2) Reduction of oxygen utilization
Nifedipine regularly reduces arterial pressure at rest and at a given level of exercise by
dilating peripheral arterioles and reducing the total peripheral vascular resistance
(afterload) against which the heart works. This unloading of the heart reduces myocardial
energy consumption and oxygen requirements, and probably accounts for the
effectiveness of nifedipine in chronic stable angina.
B) Hypertension
The mechanism by which nifedipine reduces arterial blood pressure involves peripheral
arterial vasodilatation and the resulting reduction in peripheral vascular resistance. The
increased peripheral vascular resistance that is an underlying cause of hypertension
results from an increase in active tension in the vascular smooth muscle. Studies have
demonstrated that the increase in active tension reflects an increase in cytosolic free
calcium. Nifedipine is a peripheral arterial vasodilator which acts directly on vascular
smooth muscle. The binding of nifedipine to voltage-dependent and possibly receptor-
operated channels in vascular smooth muscle results in an inhibition of calcium influx
through these channels. Stores of intracellular calcium in vascular smooth muscle are
limited and thus dependent upon the influx of extracellular calcium for contraction to
occur. The reduction in calcium influx by nifedipine causes arterial vasodilation and
decreased peripheral vascular resistance which results in reduced arterial blood pressure.
Pharmacokinetics and metabolism
Nifedipine is completely absorbed after oral administration. Plasma drug concentrations
rise at a gradual and reach a plateau at approximately six hr after the first dose.
Nifedipine is extensively metabolized to highly water-soluble, inactive metabolites,
accounting for 60 to 80% of the dose excreted in the urine. The elimination half-life of
nifedipine is approximately 2 h. Only traces (less than 0.1% of the dose) of unchanged
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 83
form can be detected in the urine. The remainder is excreted in the feces in metabolized
form, most likely as a result of biliary excretion. Thus, the pharmacokinetics of nifedipine
is not significantly influenced by the degree of renal impairment. Patients in hemodialysis
or chronic ambulatory peritoneal dialysis have not reported significantly altered
pharmacokinetics of nifedipine. Since hepatic biotransformation is the predominant route
for the disposition of nifedipine, the pharmacokinetics may be altered in patients with
chronic liver disease. Patients with hepatic impairment (liver cirrhosis) have a longer
disposition half-life and higher bioavailability of nifedipine than healthy volunteers. The
degree of serum protein binding of nifedipine is high (92–98%). Protein binding may be
greatly reduced in patients with renal or hepatic impairment.
Hemodynamics
Like other slow-channel blockers, nifedipine exerts a negative inotropic effect on isolated
myocardial tissue. This is rarely, if ever, seen in intact animals or man, probably because
of reflex responses to its vasodilating effects. In man, nifedipine decreases peripheral
vascular resistance which leads to a fall in systolic and diastolic pressures, usually
minimal in normotensive volunteers (less than 5–10 mm Hg systolic), but sometimes
larger. Hemodynamic studies in patients with normal ventricular function have generally
found a small increase in cardiac index without major effects on ejection fraction, left
ventricular end diastolic pressure (LVEDP), or volume (LVEDV). In patients with
impaired ventricular function, most acute studies have shown some increase in ejection
fraction and reduction in left ventricular filling pressure.
Electrophysiologic effects
Although, like other members of its class, nifedipine causes a slight depression of
sinoatrial node function and atrioventricular conduction in isolated myocardial
preparations, such effects have not been seen in studies in intact animals or in man. In
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 84
formal electrophysiologic studies, predominantly in patients with normal conduction
systems, nifedipine has had no tendency to prolong atrioventricular conduction or sinus
node recovery time, or to slow sinus rate.
Indication and usage
I. Vasospastic angina
Nifedipine is indicated for the management of vasospastic angina confirmed by any of the
following criteria: 1) classical pattern of angina at rest accompanied by ST segment
elevation, 2) angina or coronary artery spasm provoked by ergonovine, or 3)
angiographically demonstrated coronary artery spasm. In those patients who have had
angiography, the presence of significant fixed obstructive disease is not incompatible with
the diagnosis of vasospastic angina, provided that the above criteria are satisfied.
Procardia XL may also be used where the clinical presentation suggests a possible
vasospastic component, but where vasospasm has not been confirmed, e.g., where pain
has a variable threshold on exertion, or in unstable angina where electrocardiographic
findings are compatible with intermittent vasospasm, or when angina is refractory to
nitrates and/or adequate doses of beta blockers.
II. Chronic stable angina
Nifedipine is indicated for the management of chronic stable angina (effort-associated
angina) without evidence of vasospasm in patients who remain symptomatic despite
adequate doses of beta blockers and/or organic nitrates or who cannot tolerate those
agents. In chronic stable angina (effort-associated angina), nifedipine has been effective
in controlled trials of up to eight weeks duration in reducing angina frequency and
increasing exercise tolerance, but confirmation of sustained effectiveness and evaluation
of long-term safety in these patients is incomplete.
Controlled studies in small numbers of patients suggest concomitant use of nifedipine and
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 85
beta-blocking agents may be beneficial in patients with chronic stable angina, but
available information is not sufficient to predict with confidence the effects of concurrent
treatment, especially in patients with compromised left ventricular function or cardiac
conduction abnormalities. When introducing such concomitant therapy, care must be
taken to monitor blood pressure closely, since severe hypotension can occur from the
combined effects of the drugs.
III. Hypertension
Nifedipine is indicated for the treatment of hypertension. It may be used alone or in
combination with other antihypertensive agents.
Contraindication
Known hypersensitivity reaction to nifedipine.
Warnings
Excessive hypotension
Although in most angina patients the hypotensive effect of nifedipine is modest and well
tolerated, occasional patients have had excessive and poorly tolerated hypotension. These
responses have usually occurred during initial titration or at the time of subsequent
upward dosage adjustment, and may be more likely in patients on concomitant beta
blockers. Severe hypotension and/or increased fluid volume requirements have been
reported in patients receiving nifedipine together with a beta-blocking agent who
underwent coronary artery bypass surgery using high dose fentanyl anesthesia. The
interaction with high dose fentanyl appears to be due to the combination of nifedipine and
a beta blocker, but the possibility that it may occur with nifedipine alone, with low doses
of fentanyl, in other surgical procedures, or with other narcotic analgesics cannot be ruled
out. In nifedipine-treated patients where surgery using high dose fentanyl anesthesia is
contemplated, the physician should be aware of these potential problems and, if the
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 86
patient’s condition permits, sufficient time (at least 36 hr) should be allowed for
nifedipine to be washed out of the body prior to surgery.
The following information should be taken into account in those patients who are being
treated for hypertension as well as angina:
Increased angina and/or myocardial infarction
Rarely, patients, particularly those who have severe obstructive coronary artery disease,
have developed well documented increased frequency, duration and/or severity of angina
or acute myocardial infarction on starting nifedipine or at the time of dosage increase.
The mechanism of this effect is not established.
Beta blocker withdrawal
It is important to taper beta blockers if possible, rather than stopping them abruptly before
beginning nifedipine. Patients recently withdrawn from beta blockers may develop a
withdrawal syndrome with increased angina, probably related to increased sensitivity to
catecholamines. Initiation of nifedipine treatment will not prevent this occurrence and on
occasion has been reported to increase it.
Congestive heart failure
Rarely, patients, usually receiving a beta blocker, have developed heart failure after
beginning nifedipine. Patients with tight aortic stenosis may be at greater risk for such an
event, as the unloading effect of nifedipine would be expected to be of less benefit, owing
to the fixed impedance to flow across the aortic valve in these patients.
Gastrointestinal obstruction requiring surgery
There have been rare reports of obstructive symptoms in patients with known strictures in
association with the ingestion of nifedipine extended release tablet. Bezoars can occur in
very rare cases and may require surgical intervention. Cases of serious gastrointestinal
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 87
obstruction have been identified in patients with no known gastrointestinal disease,
including the need for hospitalization and surgical intervention.
Risk factors for a gastrointestinal obstruction identified from post-marketing reports of
Nifedipine extended release tablet include alteration in gastrointestinal anatomy (e.g.,
severe gastrointestinal narrowing, colon cancer, small bowel obstruction, bowel resection,
gastric bypass, vertical banded gastroplasty, colostomy, diverticulitis, diverticulosis, and
inflammatory bowel disease), hypomotility disorders (e.g., constipation, gastroesophageal
reflux disease, ileus, obesity, hypothyroidism, and diabetes) and concomitant medications
(e.g., H2-histamine blockers, opiates, nonsteroidal anti-inflammatory drugs, laxatives,
anticholinergic agents, levothyroxine, and neuromuscular blocking agents).
Gastrointestinal ulcers
Cases of tablet adherence to the gastrointestinal wall with ulceration have been reported,
some requiring hospitalization and intervention.
Precautions
Because nifedipine decreases peripheral vascular resistance, careful monitoring of blood
pressure during the initial administration and titration of nifedipine is suggested. Close
observation is especially recommended for patients already taking medications that are
known to lower blood pressure.
Dosage information (www.drugs.com)
Usual adult dose of nifedipine for hypertension
Initial dose
For extended release tablets: 30 to 60 mg orally once a day
Dosage can be increased gradually every 7 to 14 days.
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 88
Usual adult dose of nifedipine for migraine prophylaxis
Initial dose
For extended release tablets: 30 mg orally once a day
Immediate release capsules
10 mg orally 3 times a day
Usual adult dose of nifedipine for angina pectoris prophylaxis
Initial dose
For extended release tablets: 30 to 60 mg orally once a day
Immediate release capsules
10 mg orally 3 times a day
Review of research work done on nifedipine solubility enhancement
Lin and Cham, 1996 have prepared solid dispersion of containing 5%, 10%, 30% and
50% of nifedipine using polyethylene glycol 6000 (PEG 6000) as carrier polymer by
fusion method. They found that dissolution process were markedly enhanced in the solid
dispersions with lower contents of nifedipine (5% and 10%) due to the formation of high
energy metastable (amorphous) states of the drug and decreases in the particle sizes
which increases the available surface for dissolution of the drug.
Bayomi et al., 2002 have studied the effect of inclusion complexation with cyclodextrins
on photostability of nifedipine in solid state. In this study, they have prepared solid
inclusion complexes of nifedipine with β-cyclodextrin (β-CD), hydroxypropyl- β-
cyclodextrin (HP-β-CD) and dimethyl- β-cyclodextrin (DM-β-CD) using co precipitation
method. They confirmed the obtained solid inclusion complexes by differential scanning
calorimetry (DSC), X-ray diffraction (XRD) and infrared spectroscopy (IR) analysis.
Inclusion complexation of nifedipine showed to retard drug photo degradation as
indicated by degradation rate constant lowering with values depended on light source and
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 89
type of complexing agent. This effect was the least with β-CD compared with that of
modified β-CD. They have also found that inclusion complexation of nifedipine offered
much higher protection against the effect of fluorescent lamp than that of sunlight.
Zajc et al., 2005 have studied the physical properties and dissolution behavior of
nifedipine/mannitol solid dispersions prepared by hot melt method. In all samples, they
confirmed the crystal structure of nifedipine using differential scanning calorimetry
(DSC) and scanning electron microscopy (SEM). From Fourier transform infrared
spectroscopy (FTIR) study, they observed that there was no interaction between drug and
carrier; however, FTIR spectra indicated formation of thermodynamically less stable
polymorph of mannitol. They found that the dissolution rate of nifedipine from solid
dispersions was markedly enhanced, and the effect being stronger at higher drug loading
(50%, w/w, nifedipine). They observed that the dissolution rate enhancement was mainly
because of improved wetting of nifedipine crystals due to mannitol particles, attached on
the surface, as inspected by means of SEM. They have investigated that the thermal
stability of nifedipine, mannitol and 2 other potential carbohydrate carriers (lactose and
saccharose) using 1H NMR. Moreover, they found that nifedipine was thermically stable
under conditions applied and among all carriers only mannitol demonstrated suitable
resistance to high temperature used in experiments.
Hecq et al., 2005 have prepared and characterized the nanocrystal of nifedipine drug for
solubility enhancement. They have prepared the nanoparticles of nifedipine using high
pressure homogenization. They have characterized the nanoparticles in terms of size,
morphology and redispersion characteristics. Saturation solubility and dissolution
characteristics were investigated and compared with the un-milled commercial nifedipine
to verify the theoretical hypothesis on the benefit of increased surface area. They have
also evaluated crystalline state before and after particle size reduction through differential
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 90
scanning calorimetry (DSC) and powder X-ray diffraction (PXRD) to denote eventual
transformation to amorphous state during the homogenization process. Through this
study, it has been shown that initial crystalline state is maintained following particle size
reduction and the dissolution characteristics of nifedipine nanoparticles were significantly
increased as compared to the commercial product. They found that the developed method
was very simple and easily scaled up, and this approach can be applicable to many poorly
water-soluble drug entities.
Kamiya et al., 2008 have prepared and stabilized the Nanoparticles of nifedipine for
solubility enhancement. They designed the methods of nanoparticles formulations by
break-down and a build-up method. In addition, they divided the break down method into
dry and wet processes. They prepared nifedipine nanoparticles without using any organic
solvent in high-pressure homogenization with a mean particle size of approximately 50
nm. To maintain the particle size of the nanoparticles in suspension for a long time, a
method of adding gelatin powder to the nifedipine-lipid nanoparticles suspension,
dissolving the mixture by heating, and then solidifying by cooling was also been studied.
They observed that the mean particle size of the sample was about 55 nm, and that after
heat-liquefaction of the NI-lipid nanoparticle suspension gelated at 5 ◦C for 24 h was also
about 55 nm, showing that the nanoparticle condition was retained.
Ohshima et al., 2009 have prepared the freeze-dried nifedipine-lipid nanoparticles and
improved its long-term stability after reconstitution. The mean particle size of freeze-
dried nifedipine-lipid nanoparticles after reconstitution was significantly increased in
comparison to that of the preparations before freeze-drying. So, they concducted different
studies and found that the addition of sugars (glucose, fructose, maltose or sucrose) to the
suspensions before freeze-drying can minimize the aggregation of nanoparticles. In
addition, freeze-dried nanoparticles with 100mg sugar (glucose, fructose, maltose or
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 91
sucrose) showed excellent solubility (>80%), whereas without sugar, showed low
solubility (<20%). So, they concluded that negatively charged phospholipids and sugars
prevent coagulation of nifedipine nanoparticle suspensions, and surprisingly increase the
apparent solubility of nifedipine.
Yang and Villiers, 2004 have studied the solubilizing effect of 4-sulphonic
calyx[n]arenes on the poorly water soluble drug nifedipine. 4- Sulphonic calix[n ]arenes
are water-soluble phenolic cyclooligomers that form complexes with neutral molecules
such as nifedipine. They have performed the solubility experiments at 30°C using the
Higuchi rotating bottle method. From results they found that the size of the 4-sulphonic
calix[n]arenes, the pH of solubility medium, and the concentration of the calix[n]arenes
all significantly changed the solubility of nifedipine. They observed that 4-Sulphonic
calix[8]arene improved the solubility of nifedipine the most, about 3 times the control at
pH 5, followed by 4-sulphonic calix[4]arene, about 1.5 times the control at pH 5, while in
the presence of 4-sulphonic calix[6]arene, the solubility of nifedipine was decreased.
Wu et al., 2012 have prepared the solid dispersions of nifedipine prepared with 2
hydrophilic carrier systems, Gelucire (44/14)/PEG 600 and PVP (K12-K25)/ PEG 6000
by fusion or fusion/solvent method to improve the solubility of nifedipine. From
dissolution tests they further demonstrated that nifedipine, once fused with these carriers,
possessed an enhanced dissolution rate. Moreover, in case of Gelucire (44/14)/PEG 600
as a carrier system, the dissolution rates were faster than sample which prepared by
melting method of Gelucire. So, they conclude that the dissolution rate increased with the
amount of Gelucire added in the preparation. For the PVP/PEG 6000 carrier system, the
dissolution rate of nifedipine increased with the amounts of both PVP and PEG 6000.
Moreover, a slower dissolution rate was also noted resulted from higher molecular weight
of PVP.
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 92
Lalitha and Lakshmi, 2011 have evaluated the surface solid dispersion technology to
enhance the dissolution of nifedipine. They optimized the formulations in the preliminary
trials using various ratios of different carriers like kyron T‐314, croscarmellose sodium,
crospovidone, silicified microcrystalline cellulose and sodium starch glycolate. They have
evaluated the formulations using FTIR, X‐ray diffraction, DSC, GC, SEM and in vitro
dissolution. From dissolution studies, they found that solid dispersion prepared with
kyron T‐314 at 1:9 ratio gave good release as compared to pure drug and physical
mixtures. They found that the sublingual tablets prepared with kyron T‐314 as
disintegrants gave good disintegration.
Jagdale et al., 2012 have prepared the fast-dissolving tablet of nifedipine-
betacyclodextrin complexes to enhance the dissolution of nifedipine. From stoichiometric
and phase solubility studied they have optimized the ratio of nifedipine with β-
cyclodextrin. They prepared binary complex by different methods and further
characterized it using XRD, DSC and FT-IR. They performed the saturation solubility
study to evaluate the increase in solubility of nifedipine. They formulated the optimized
complex into fast-dissolving tablets by using the superdisintegrants like as Doshion P544,
pregelatinized starch, crospovidone, sodium starch glycolate and croscarmellose sodium
by direct compression method. Moreover, they concluded that the optimized tablets
showed an enhanced dissolution rate compared to pure nifedipine.
Datta et al., 2011 have improved the solubility of nifedipine by solid dispersion method.
They prepared the solid dispersion by solvent evaporation method using HP-β-CD and
different concentration of SLS as carrier polymer. From physicochemical characterization
by DSC analysis they discovered that, the enhancing effect of SD on the dissolution was
mainly attributed to the transformation of nifedipine into the amorphous state.
Improvement of increased solubility also contributed to the result. In addition, the IR
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 93
spectra indicated the possible intermolecular hydrogen bonding between the drug and the
carriers.
Yen et al., 1997 have improved the dissolution rate of nifedipine by means of deposition
on superdisintegrants using solvent deposition technique. They have used different super
disintegrants like Ac-Di-Sol, Kollidon CL, and Explotab. They investigated the relative
significance of action of solvent deposition (deposition of small drug particles on the
excipient after solvent is evaporated) and action of superdisintegrant on dissolution of
nifedipine. They have used differential scanning calorimetry (DSC) to study the
interaction between nifedipine and superdisintegrants. From dissolution study they
revealed that solvent deposition system with lactose and super disintegrants in capsule
and tablet dosage forms can significantly enhance dissolution rate of nifedipine.
Nagarajan et al., 2010 have also improved the solubility of nifedipine by solid
dispersion method. They used common solvent evaporation method and melting fusion
method for the preparation of solid dispersion in different drug: carrier ratios (9:1, 3:1,
1:1, 1:3, 1:9) using polyethylene glycol (PEG 4000) to enhance the solubility of
nifedipine. They confirmed no interaction between drug and carrier by TLC and IR
spectroscopic studies. They observed that Rf value of prepared dispersions was similar to
that of the pure drug (0.18) in UV light without any extra spots indicated that there was
no interaction between the drug and carrier polymer. In addition, the IR result of the
prepared dispersions showed no interactions between the drug and carrier.
Aparna et al., 2010 have improved the dissolution rate of nifedipine by solvent
evaporation based solid dispersion technique. They formulated the solid Dispersions of
nifedipine with four different polymers like as hydroxypropylcellulose (HPC),
polyvinylpyrrolidone K 29/32 (PVP K 29/32), polyethylene glycol 6000 (PEG 6000) and
gelucire 44/14 in six different ratios. Moreover, to prepare solid dispersions with PEG
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 94
6000 they have used both melting and solvent method. They have also used the
combination of PEG 6000 and Gelucire 44/14, as well as PVP K 29/32 and Gelucire
44/14 polymer. They have used dissolution studies, DSC, FT-IR and stability studies for
proper evaluation of solid dispersions. Finally, they observed that HPC and PVP K 29/32
solid dispersions gave higher dissolution rate than other solid dispersions and the
combination solid dispersions do not markedly enhance dissolution.
Vippagunta et al., 2002 have prepared and characterized the nature and solid-state
properties of a solid dispersion system of nifedipine (33.3% w/w) in a polymer matrix
consisting of Pluronic F68 (33.3% w/w) and Gelucire 50/13 (33.3% w/w). They studied
the nature of nifedipine dispersed in the matrix by powder X-ray diffractometry (PXRD),
differential scanning calorimetry (DSC) and diffuse reflectance infrared Fourier transform
spectroscopy (DRIFTS). They also studied the rate and extent of water uptake of the solid
dispersion by weight gain. They conclude that the nifedipine solid dispersion is physically
stable over 8 weeks as well as nifedipine released was faster in the solid dispersion than
the pure crystalline drug of the same particle size.
Cilurzo et al., 2008 have prepared fast dissolving microparticles of nifedipine using
poly(sodium methacrylate, methyl methacrylate) (NaPMM), a novel mucoadhesive
material. Microparticles made of a low-viscosity hydroxypropylmethylcellulose (HPMC),
were also prepared to compare the NIF release profile and bioadhesive properties. They
have also carried out the release test in oversaturation conditions as well as also studied
the physical state of microparticles. They evaluated the formulation stability over a 3-
months period in long-term and accelerated conditions. They observed that NaPMM
conferred to microparticles suitable mucoadhesive properties and significantly increased
nifedipine dissolution rate in comparison to HPMC. They observed that nifedipine
dissolution rate and supersaturation degree significantly decreased due to drug
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 95
crystallization after 3 months storage in the case of HPMC microparticles. Moreover, in
case of NaPMM microparticles, neither nifedipine dissolution rate nor apparent solubility
was significantly changed.
Kolima et al., 2012 have studied the effects of spray drying process parameters on the
solubility behavior and physical stability of solid dispersions prepared using a laboratory-
scale spray dryer. From results they observed that solubility behavior and physical
stability were improved by setting the low nitrogen flow rate and high sample
concentration. So, they concluded that nitrogen flow rate and sample concentration
should be the critical parameters for the enhancements of the solubility and physical
stability of solid dispersions.
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 96
2.3.1 References
1. Lin CW and Cahm TM. Effect of particle size on the available surface area of nifedipine
from nifedipine-polyethylene glycol 6000 solid dispersions. Int J Pharm Sci Drug Res
1996;127:261-72
2. Vippagunta SR, Maul KA, Tallavajhala S, Grant DJW. Solid-state characterization of
nifedipine solid dispersions. Int J Pharm 2002;236:111-23
3. Blagden N, Matas M, Gavan PT, York P. Crystal engineering of active pharmaceutical
ingredients to improve solubility and dissolution rates. Adv Drug Deliv Rev 2007;59:617-
30
4. Yu L, Amorphous pharmaceutical solids: preparation, characterization and stabilization,
Adv Drug Deliv Rev 2001;48:27–42
5. Bayomi MA, Abanumay KA, Al-Angary AA. Effect of inclusion complexation with
cyclodextrins on photostability of nifedipine in solid state. Int J Pharm 2002;243:107-17
6. Zajc N, Obreza A, Bele M, Srcic S. Physical properties and dissolution behaviour of
nifedipine/mannitol solid dispersions prepared by hot melt method. Int J Pharm
2005;291:51-8
7. Hecq J, Deleers M, Fanara D, et al. Preparation and characterization of nanocrystals for
solubility and dissolution rate enhancement of nifedipine. Int J Pharm 2005;299:167-77
8. Kamiya S, Yamada M, Kurita T, et al. Preparation and stabilization of nifedipine lipid
nanoparticles. Int J Pharm 2008;354:242-7
9. Ohshima H, Miyagishima A, Kurita T, et al. Freeze-dried nifedipine-lipid nanoparticles
with long-term nano-dispersion stability after reconstitution. Int J Pharm 2009;377:180-4
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 97
10. Yang W and Villiers MM. The solubilization of the poorly water soluble drug nifedipine
by water soluble 4-sulphonic calix[n]arenes. Eur J Pharm Biopharm 2004:58:629-36
11. Pottarino F, Giovannelli L, Bellomi S. Effect of poloxamers on nifedipine microparticles
prepared by Hot Air Coating technique. Eur J Pharm Biopharm 2007;65:198-203
12. Cilurzo J, Selmin F, Minghetti P, et al. Characterization and physical stability of fast-
dissolving microparticles containing nifedipine. Eur J Pharm Biopharm 2008;68:579-88
13. Wu JY, Oho H, Chen Y, et al. Thermal analysis and dissolution characteristics of
nifedipine solid dispersions. J Food Drug Analysis 2012;20:27-33
14. Lalitha Y and Lakshmi PK. Enhancement of dissolution of nifedipine by surface solid
dispersion technique. Int J Pharm Pharmaceutical Sci 2011;3:41-6
15. Jagdale SC, Jadhav VN, Chabukswar AR, et al. Solubility enhancement, physicochemical
characterization and formulation of fast-dissolving tablet of nifedipine-betacyclodextrin
complexes. Brazilian J Pharm Sci 2012;48:132-45
16. Datta A, Ghosh NS, Ghosh S, et al. Development, characterization and solubility study of
solid dispersion of nifedipine by solvent evaporation method using poloxamer 407. Int J
App Bio Pharma Technol 2011;2:1-7
17. Datta A, Ghosh NS, Ghosh S, et al. Development, characterization and solubility study of
solid dispersion of nifedipine by solvent evaporation method using β-cyclodextrin. J Adv
Pharm Res 2011;2:81-4
18. Yen SY, Chen CR, Lee MT, Chen LC. Investigation of dissolution enhancement of
nifedipine by deposition on superdisintegrants. Drug Dev Ind Pharm 1997;23:313-7
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 98
19. Kojima Y, Ohta T, Shiraki K, et al. Effects of spray drying process parameters on the
solubility behavior and physical stability of solid dispersions prepared using a laboratory-
scale spray dryer. Drug Dev Ind Pharm 2012;Jun 7:Article in press
20. Nagarajan K, Rao MG, Dutta S, et al. Formulation and dissolution studies of solid
dispersions of nifedipine. Indian J Novel Drug Del 2010;2:96-8
21. Aparna K, Meenakshi B, Monika S. Improvement of dissolution rate and solubility of
nifedipine by formulation of solid dispersion. The Pharm Res 2010;4:38-50
22. www.drugs.com
23. www.medlineplus.com
24. Nifedipine capsule. USP monograph. USP 32. NF 27
25. Shelke OS, Sable KS, Neharkar VS, Mathdevru BV. Development and validation of UV
spectrophotometric method for simultaneous determination of nifedipine and Atenolol in
combined dosage form. Int Res J Pharm 2012;3:360-4
26. Raja AM, Kumar SD, Kumar MS, et al. Spectrophotometric estimation of nifidipine by
using various solvents. Int Res J Pharm 2010;1:20-23
27. Product information leaflet. Procardia XL (nifedipine) capsule for oral use
28. Martins RM, Machado MO, Pereira SV, et al. Microparticulated hydrochlorothiazide
solid dispersion: enhancing dissolution properties via spray drying. Drying Technol
2012;30:959-67
29. Lachman L; Lieberman HA; Kaing JL. The theory and practice of industrial pharmacy.
4th
edition New Delhi: CBS Publication, 1991. p.66-99.
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 99
2.4 Furosemide
Description
Furosemide is a 5- (aminosulfonyl)-4-chloro-2-[(furanylmethyl) amino] benzoic acid and
is a diuretic and antihypertensive drug, practically insoluble in water (10 µg/mL) and
belongs to BCS Class IV. Furosemide is a loop diuretic commonly used in the treatment
of edematous states associated chronic renal failure, hypertension, congestive heart failure
and cirrhosis of the liver [Kanyak et al., 2013]. The rate of absorption and the extent of
bioavailability for such an insoluble hydrophobic drug is controlled by the rate of
dissolution in the gastrointestinal fluid and has the structural formula as:
Figure 2.11 Chemical structure of furosemide
Chemical name: 4-Chloro-N-furfuryl-5-sulphamoylanthranilic acid; 5-(Aminosulfonyl)-
4-chloro-2-[(2-furanylmethyl) amino] benzoic acid; 4-Chloro-N-(2-furylmethyl)-5-
sulfamoylanthranilic acid
Physical description
Appearance White or slightly yellow
State Solid-crystals or solid powder
Melting point 202-204°C
Molecular formula C12H11ClN2O5S
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 100
Molecular weight 330.7
Solubility Odourless and practically insoluble in water; very slightly soluble in
chloroform; soluble in alcohol; slightly soluble in ether; freely soluble in acetone;
dimethylformamide; methyl alcohol and solutions of alkali hydroxides with pKa is 3.9 at
20°C [International Programme on Chemical Safety; Inchem; www.ipcs.com].
Clinical pharmacology
Furosemide (Figure 2.11) is a loop diuretic used in adults, infants and children for the
treatment of edema associated with congestive heart failure, cirrhosis of the liver and
renal disease. Oral furosemide may be used in adults for the treatment of hypertension of
alone or in combination with other antihypertensive agents (3-5). The therapy should be
individualized according to patient response to gain maximal therapeutic response and to
determine the minimal dose needed to maintain that response. The usual dose of
furosemide in edema is 20 to 80 mg given as a single dose. If needed, the same dose can
be administered 6 to 8 hr later or the dose may be increased (4-6). In the case of
hypertension, the usual initial dose is 80 mg, usually divided into 40 mg twice as day
Mechanism of action
Furosemide diuresis increases the excretion of sodium; chloride; potassium; hydrogen;
calcium; magnesium; ammonium and bicarbonate. The depletion of these electrolytes is a
major cause of toxicity effects. For example; low potassium (and chloride) levels increase
the cardiac toxicity of digitalis. Excessive loss of hydrogen; potassium and chloride may
cause metabolic acidosis. A hypotensive reaction may occur from decreased plasma
volume; following excessive diuresis.
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 101
Pharmacodynamics
The exact mode of action of furosemide has not been fully defined. Furosemide primarily
inhibits sodium and chloride absorption in the thick ascending limb of the loop of Henle.
The action of furosemide is best seen in the context of the mechanism of reabsorption of
salts (NaCl in particular) and water; particularly the different points at which reabsorption
takes place within the renal tubule. Furosemide acts by reducing the osmotic pull around
the thin descending limb through inhibiting the active transport mechanism of salt
escaping via the wall of the thick ascending limb. This action reduces reabsorption of salt
(NaCl) and hence the concentration of salt around the thin descending limb is also
reduced. This in turn reduces the amount of water reabsorbed out of the thin descending
limb; with the result that more water is excreted as urine.
A consequence of this inhibition of the re-uptake of NaCl in the ascending limb is that
more NaCl than normal reaches the distal convoluted tubule and the collecting duct. At
both these points Na+ is reabsorbed by active transport and the Cl- is left in the tubule.
The negative Cl- then attracts positive K+ and H+ ions from the surrounding tissue. These
ions remain in the fluid; passing into the bladder and are lost in the urine. Hence
furosemide is a potassium depleting diuretic. Furosemide is an inhibitor of carbonic
anhydrase but the effect is not strong enough to contribute to proximal diuresis except at
very large doses. The diuretic effects of furosemide are independent of the acid-base
balance of the patient.
Pharmacokinetics and metabolism
Due to its weak acidic properties [pKa=3.9; (7)], furosemide is mostly absorbed from
stomach and upper small intestine. Bioavailability of furosemide from tablets varies from
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 102
37% to 70%. Plasma peak concentration (Cmax) is occurred between 48-90 min. The
plasma half-life (t1/2) of furosemide in healthy subjects is about 30-90 min.
Indication and usage
Edema
Furosemide is indicated in adults and pediatric patients for the treatment of edema
associated with congestive heart failure, cirrhosis of the liver, and renal disease,
including the nephrotic syndrome. Furosemide is particularly useful when an agent
with greater diuretic potential is desired.
Hypertension
Oral furosemide may be used in adults for the treatment of hypertension alone or in
combination with other antihypertensive agents. Hypertensive patients who cannot be
adequately controlled with thiazides will probably also not be adequately controlled with
furosemide alone.
Adverse effects
Hypovolemia was seen as the main adverse (dose-related) effect associated with
furosemide in a hospital drug surveillance program involving 123 patients with a total of
177 adverse reactions with furosemide. Hypovolemia occurred in 85 cases. The excessive
dehydration which may occur in geriatric patients and in patients with chronic heart
disease (with long-term sodium restriction); who are being treated with furosemide; may
give rise to hypovolaemia and consequential serious complications such as circulatory
collapse and potentially fatal vascular thromboses and/or emboli. In rare instances; death
has occurred; following parenteral administration of furosemide.
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 103
Warning
Excessive dose of furosemide
Patients with either acute or chronic overdosage with furosemide may show signs of
dehydration with thirst; lethargy; confusion; poor skin turgor; and prolonged capillary
refill time; but may have a paradoxical continued diuresis. Electrolyte abnormalities will
include hyponatremia; hypokalemia; and hypochloremia and in large ingestions may lead
to further deterioration in mental status; seizures; electrocardiographic abnormalities; and
arrhythmias. Prior renal insufficiency will lead to more toxicity at a given dose.
Hypokalemia may lead to muscular weakness; hyporeflexia; and contribute to
hypochloremic metabolic alkalosis (the so-called "volume contraction metabolic
alkalosis"). Cardiac arrhythmias may occur due to potassium deficiency and/or coexistent
hypomagnesemia. Gastrointestinal bleeding has been reported in patients taking
frusemide; especially if renal insufficiency is present. Abuse or overdose may result in
pancreatitis. Hyperglycemia; hyperuricemia; and hyperlipidemia may occur with acute
overdose or in chronic use or abuse. Hypersensitivity reactions such as rash;
photosensitivity; thrombocytopenia; and pancreatitis are rare.
Dosage information (source: product information leaflet; Lasix®)
Dosage
Edema
Therapy should be individualized according to patient response to gain maximal
therapeutic response and to determine the minimal dose needed to maintain that response.
Adults
The usual initial dose of furosemide is 20 to 80 mg given as a single dose. Ordinarily a
prompt diuresis ensues. If needed, the same dose can be administered 6 to 8 hr later or the
dose may be increased. The dose may be raised by 20 or 40 mg and given not sooner than
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 104
6 to 8 hr after the previous dose until the desired diuretic effect has been obtained. The
individually determined single dose should then be given once or twice daily (e.g., at 8
am and 2 pm). The dose of Lasix may be carefully titrated up to 600 mg/day in patients
with clinically severe edematous states.
Edema may be most efficiently and safely mobilized by giving furosemide on 2 to 4
consecutive days each week. When doses exceeding 80 mg/day are given for
prolonged periods, careful clinical observation and laboratory monitoring are
particularly advisable
Geriatric patients
In general, dose selection for the elderly patient should be cautious, usually starting at
the low end of the dosing range
Pediatric patients
The usual initial dose of oral furosemide in pediatric patients is 2 mg/kg body weight,
given as a single dose. If the diuretic response is not satisfactory after the initial dose,
dosage may be increased by 1 or 2 mg/kg no sooner than 6 to 8 hr after the previous dose.
Doses greater than 6 mg/kg body weight are not recommended. For maintenance therapy
in pediatric patients, the dose should be adjusted to the minimum effective level.
Hypertension
Therapy should be individualized according to the patient’s response to gain
maximal therapeutic response and to determine the minimal dose needed to
maintain the therapeutic response.
Adults
The usual initial dose of furosemide for hypertension is 80 mg, usually divided into 40
mg twice a day. Dosage should then be adjusted according to response. If response is not
satisfactory, add other antihypertensive agents. Changes in blood pressure must be
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 105
carefully monitored when furosemide is used with other antihypertensive drugs,
especially during initial therapy.
Review of research work done on furosemide solubility enhancement
Shin et al., 1998 have carried out research to increase the dissolution rate of furosemide
by cogrinding or coprecipitating of furosemide with crospovidone. The 1:2 (w:w) ground
mixture of furosemide with crospovidone was prepared by cogrinding in a ceramic ball
mill and the coprecipitate was prepared by the solvent method using methanol. They have
perfomed dissolution test in simulated gastric fluids (pH 1.2) and observed that the
dissolution rate of furosemide was rapid and markedly enhanced by cogrinding or
coprecipitating with crospovidone. They conclude that cogrinding or coprecipitating
techniques with crospovidone provide a promising way to increase the dissolution rate of
poorly soluble drugs.
Akburga et al., 1988 have prepared furosemide – PVP Solid Dispersion by co-
evaporation and freeze-drying methods. In X-ray diffraction patterns they observed that
furosemide in the coprecipitates was in amorphous form. The dissolution rate of
furosemide was markedly increased in these solid dispersion systems. The increase in
dissolution was a function of the ratio of drug to PVP used. With 1:7 ratio the best result
was obtained. The 49000 mol. wt. PVP yielded the most rapid furosemide dissolution.
Dissolution studies have shown that coprecipitate of furosemide-PVP (1:7) is the best
combination. They observed that the increase in release rates was attributed to the
increased wettability, coacervate formation and the complexation.
Singh et al., 2011 had improved the solubility and dissolution rate of a poorly water-
soluble drug, furosemide, by solid dispersion technique as well as evaluate the potential
of EUDRAGIT® RL 100, EUDRAGIT
® RS 100 and EUDRAGIT
® S 100 (methacrylic
acid co-polymers) as carriers for solid dispersions. They have prepared solid dispersions
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 106
by solvent evaporation technique and characterized it for particle size, particle size
distribution, solubility studies and interaction studies such as FTIR spectroscopy.
Takarkhede et al., 2012 have developed a sustained release gastroretentive beads
containing furosemide inclusion complex. The different formulations of floating beads
were prepared by using swellable mucoadhesive polymers (sodium alginate and
hydroxypropyl methylcellulose) and sodium bicarbonate as an effervescent agent. The
prepared beads were coated with different concentration of chitosan HCl solution and
evaluated for encapsulation efficiency, loading efficiency, mucoadhesion, swelling,
floating properties, particle size, in vitro release characteristic and surface morphology.
They found that the floating beads showed a promising gastroretentive drug delivery for
furosemide.
Chaulang et al., 2008 have enhanced the dissolution profile of furosemide using solid
dispersion (SD) with crospovidone (CPV) by kneading technique. They have prepared 1:1
(w/w) and 1:2 (w/w) solid dispersions by kneading method using water and ethanol in 1:1
ratio. Dissolution studies using the USP paddle method were performed for solid
dispersions of furosemide at 50 rpm in simulated gastric fluid (SGF) of pH 1.2. IR
spectroscopy, XRD, and DSC showed change in the crystal structure towards amorphous
one of furosemide (FRSD). Dissolution of furosemide improved significantly by 5.11 fold
and exhibited better dissolution profile than commercial tablets.
Jain et al., 2010 have prepared gastroretentive floating drug delivery systems (GFDDS)
of furosemide, using Hydroxypropyl methyl cellulose of different viscosity grades (K4M
and K100M) and sodium bicarbonate as gas generating agent. The tablets were prepared
by direct compression method. Estimation of furosemide in the prepared tablet
formulations was carried out with 0.1N HCl. They have evaluated the prepared
formulations for hardness, friability, weight variation, drug content uniformity, swelling
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 107
index, in vitro drug release pattern, short-term stability and drug excipient interactions.
They found more than 80% drug release in 10 hr and remained buoyant more than 24 hr.
Patel et al., 2010 have prepared prepare solid dispersion of furosemide with poly
ethylene glycol (PEG) 6000 containing microcrystalline cellulose (MCC) as adsorbent
which would dissolve completely in less than 30 min (target selected by considering
minimum gastric empting time). They conclude that similar attempts improve
bioavailability and consequently dose reduction would possible.
Akinlade et al., 2010 has developed liquisolid technology to enhance the in vitro
dissolution properties of the practically water insoluble loop diuretic furosemide. Several
liquisolid tablets were prepared using microcrystalline cellulose (Avicel pH-101) and
fumed silica (Cab-O-Sil M-5) as the carrier and coating materials, respectively.
Polyoxyethylene- polyoxypropylene-polyoxyethylene block copolymer (Synperonic PE/L
81); 1,2,3-propanetriol, homopolymer, (9Z)-9-octadecenoate (Caprol PGE-860) and
polyethylene glycol 400 (PEG 400) were used as non- volatile water-miscible liquid
vehicles. The ratio of carrier to coating material was kept constant in all formulations at
20 to 1. The formulated liquisolid tablets were evaluated for post compaction parameters
such as weight variation, hardness, drug content uniformity, % friability and
disintegration time.
Rathod et al., 2012 has used mixed solvency concept in formulation be poorly water
soluble drug. This is phenomenon of increase in solubility of poorly soluble drugs by the
addition of more than one solubilizing agent. This concept is to enhance the solubility of
furosemide in ethyl acetate and to make ethyl acetate a strong solvent for emulsification
solvent evaporation process by the use of solubilizer and limit the use of toxic organic
solvents. They found that the study may be reduce the individual concentration of
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 108
solubilizer and so reduce their toxicity and it may be provide environmentally friendly
methods.
Patel et al., 2008 have improved solubility and dissolution rate of a poorly water-soluble
drug, furosemide, by a solid dispersion technique. They had prepared solid dispersions
using polyethylene glycol 6000 (PEG 6000) and polyvinylpyrrolidone K30 (PVP K30) in
different drug-to-carrier ratios. Dispersions with PEG 6000 were prepared by fusion-
cooling and solvent evaporation, while dispersions containing PVP K30 were prepared by
solvent evaporation technique. Solid state characterizations indicated that furosemide was
present as an amorphous material and entrapped in polymer matrix. Solid dispersion
prepared with PEG showed the most improvement in wettability and dissolution rate of
furosemide.
Ozdemir et al., 1998 have increased the solubility of furosemide by inclusion compound
of b-cyclodextrin (bCD). They have studied the interaction between FR and b-CD in
solution by the solubility method. Inclusion complex of 1:l molar ratio were prepared by
freeze-drying, kneading, and co-precipitation methods. In addition, the physical mixture
was prepared for comparison. They observed that the dissolution rate of FR was
significantly enhanced by inclusion of the b-CD in the formulations.
Patel et al., 2011 have prepared solid dispersion of furosemide using different
concentration of polyethylene glycol 4000 (PEG 4000). The effect of solvent method of
preparation of different solid dispersion on dissolution behavior was also investigated.
The dissolution rate of furosemide was significantly increased with PEG 4000. Solid
dispersions containing furosemide/PEG 4000(1:5) showed 92.415% increase in
dissolution after 30 min in 0.1 N HCl as compared with pure drug. Technique of solid
dispersion tablet of furosemide which can be scaled-up industrially is promising approach
for enhancing solubility and dissolution rate.
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 109
Agrawal et al., 2007 have prepared solid complexes of furosemide with humic acid and
observed significant improvement in dissolution. They found that optimizecd complex in
1:2 ratio showed significant improvement in diuresis in man wistar rats. They conclude
that humic acid has the potential to increase the bioavailability of poorly water soluble
drugs.
Deshmukh et at., 2010 have developed the self microemulsifying drug delivery system
(SMEDDS) of furosemide. Furosemide is Class IV molecule according to BCS having
low solubility and low permeability. Prepared optimized SMEDDS of furosemide
composed of Captex® 500 as oil and Cremophore EL as surfactant in 20:80 ratio. They
found that the optimized SMEDDS of furosemide showed increase in dissolution rate of
furosemide in simulated gastric fluid (SGF) and 5.8 pH phosphate buffer, irrespective of
pH compared the marketed tablet Lasix® (furosemide 40 mg).
Chaulang et al., 2009 have prepared solid dispersion of furosemide in SSG by kneading
method. They had characterized it by Fourier transform infrared (FTIR) spectroscopy,
differential scanning calorimetry (DSC), and X-ray diffraction (XRD) and dissolution
characteristics in simulated gastric fluid (pH 1.2). From dissolution data they observed
that furosemide dissolution was enhanced. So, XRD, DSC, FTIR spectroscopy and
dissolution studies indicated that the solid dispersion formulated in 1:2 ratio showed a
5.40-fold increase in dissolution and also exhibited superior dissolution characteristics to
commercial furosemide tablets.
Zordi et al., 2012 have reported of improvement in the in vitro bioavailability of
furosemide through particle size reduction as well as formation of solid dispersions (SDs)
using the hydrophilic polymer crospovidone. Supercritical carbon dioxide was used as the
processing medium for these experiments. Micronization by means of SAS at 200 bar
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 110
resulted in a significant reduction of crystallites, particle size, as well as improved
dissolution rate in comparison with untreated drug.
Perioli et al., 2012 have improved solubility of furosemide by the furosemide (FURO)
intercalation into the inorganic matrix hydrotalcite (MgAl-HTlc), and its successive
formulation in tablets intended to be swallowed whole and to disintegrate rapidly in the
stomach. These formulations were prepared by direct compression of a simple powder
mixture constituted by MgAl-HTlc-FURO, a super disintegrants (Explotab, Polyplasdone
XL, Polyplasdone XL-10, L-HPC LH-21) and a filler.
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 111
2.4.1 References
1. Kanyak MS, Sahin S. Development and validation of RP HPLC method for determination
of solubility of furosemide. Turk J Pharm Sci 10 (1); 2013: 25-34.
2. LASIX. Product information leaflet. 2010 sanofi-aventis U.S. LLC
3. Shin SC, Oh IJ, Lee Y, Choi HK, Choi JS. Enhanced dissolution of furosemide by
coprecipitating or cogrinding with crospovidone. Int J Pharm 175; 1998: 17–24.
4. Akbuga J, Gursoy A, Kendi E. The preparation and stability of fast release furosemide –
PVP solid dispersion. 1988; 14 (10): 1439-1464.
5. Singh G, Pai RS, Kusumdevi V. Effect of the EUDRAGIT® and Drug coat on the release
behavior of poorly soluble drug by solid dispersion technology. Int J Pharm Sci Res.
2011;2(4):816-824.
6. Takarkhede K, Singhavi DJ, Khan S, Yeole P. Floating and mucoadhesive system of
furosemide: development and in vitro evaluation. Thai J Pharm Sci. 2012; 36: 12-23.
7. Chaulang G, Patil K, Ghodke D, Khan S, Yeole P. Preparation and characterization of
solid dispersion tablet of furosemide with crospovidone. Research J Pharm Tech. 2008;
1(4): 386-389.
8. Jain D, Verma S, Shukla SB, Jain AP, Yadav P. Formulation and evaluation of
gastroretentive tablets of furosemide (Evaluation based on drug release kinetics and
factorial designs). J. Chem. Pharm. Res., 2010; 2(4): 935-978.
9. Patel RC, Patel NM, Patel MM. Logical formulation development for furosemide
dissolution enhancement by preparing solid dispersion containing adsorbent. Der
Pharmacia Lettre. 2010; 2(2): 74-81.
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 112
10. Akinlade B. Elkordy AA, Essa EA, Elhagar S. Liquisolid systems to improve the
dissolution of furosemide. Scientia Pharmaceutica. 2010; 78: 325-344.
11. Rathod M, Agrawal S, Lodhi BS. Formulation of furosemide microspheres made by
Mixed Solvency Concept. Int J Pharmaceutical & Biological Arch 2012; 3(4): 744-746.
12. Patel RP, Patel DJ, Bhimani D, Patel JK. Physicochemical characterization and
dissolution study of solid dispersions of furosemide with polyethylene glycol 6000 and
poly vinyl pyrrolidone K30. Dissolution Technologies; AUGUST 2008; 17-25.
13. Ozdemir N, Ordu S. Improvement of dissolution properties of furosemide by
complexation with b-cyclodextrin. Drug Development and Industrial Pharmacy, 1998;
24(l): 19-25.
14. Patel A, Prajapati P, Boghara R, Shah D. Solubility enhancement of poorly water soluble
furosemide using PEG 4000 by solid dispersion. Asian J Pharm Sci Clinical Res 2011;
1(2): 1-9.
15. Agrawal SP. Aqil M, Anwar K. Enhancement of dissolution and diuretic effect of
furosemide through a novel complexation with humic acid extracted from shilajit. Asian
J. Chem. 2007; 19(6): 4711-4718.
16. Deshmukh A, Nakhat P, Yeole P. Formulation and in-vitro evaluation of self
microemulsifying drug delivery system (SMEDDS) of furosemide. Der Pharmacia Lettre,
2010; 2(2): 94-106.
17. Chaulang G, Patel P, Hardikar S, Kelkar M, Bhise S. Formulation and evaluation of solid
dispersions of furosemide in sodium starch glycolate. Tropical J Pharm Res. 2009; 8(1):
43-51.
Chapter 2 Literature Review
Patel Bhavesh Babulal Ph. D Thesis Page 113
18. Zordi ND, Moneghini M, Kikic I, et al. Applications of supercritical fluids to enhance the
dissolution behaviors of furosemide by generation of microparticles and solid dispersions.
Eur J Pharm Biopharm. 2012; 81: 131–141.
19. Perioli L, D’Alba G, Pagano C. New oral solid dosage form for furosemide oral
administration. Eur J Pharm Biopharm. 2012; 80: 621-629.