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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



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]



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



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



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



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



“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].



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].



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



Figure 2.3 Critical process and formulation variables in spray drying technology



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



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 -



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.



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



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



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].



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



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].



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



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



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.



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



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,



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



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



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.



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



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



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



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]



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]



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]



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]



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]



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



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,



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.



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



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



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



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]



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



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



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



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



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



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



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



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



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



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



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



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



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


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



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



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


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



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



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



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



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.



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



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



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











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.


L 100


Production process Emulsion polymerization and subsequent spray drying



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











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.


RL PO


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



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



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.



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



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



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



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



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



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.



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



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



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



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.



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



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



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



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.



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



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



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.



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



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.



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



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.



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



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



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



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



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



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.



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



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.



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.



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.



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.

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