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Formulation Development Techniques of Co-processed
Excipients
Ajay Subhash Chougule,* Amrita Dikpati and Tushar Trimbake
AISSMS College of pharmacy, Kennedy Road, Near R.T.O., Pune-01,
India.
Email: [email protected] Mob. No- 9404953361
Introduction: In recent years drug formulation scientists
have recognized that single-component excipients do not always
provide the requisite performance to allow certain active
pharmaceutical ingredients to be formulated or manufactured
adequately. In response to these deficiencies, drug formulation
scientists have relied on increasing number of combination
excipients introduced by excipient manufacturers into the
commercial market. Combination excipients fall into two broad
categories: physical mixtures and co-processed excipients.
Physical mixtures, as the name suggests, are simple admixtures
of two or more excipients typically produced by short duration
low-shear processing. They may be either liquids or solids and are
generally used for convenience rather than for facilitating the
manufacturing process or
improving the resultant pharmaceutical product. Examples of such
physical mixtures include immediate-release film coating powders
for dispersion that reduce the time required to prepare film
coating suspensions and to minimize color variation of the final
product. Such physical mixtures are not appropriate for
consideration for National Formulary (NF) monographs because the
individual components are isolated (distinct and intact) before
mixing; i.e., the manufacturing process of each of the individual
components has been taken to completion, and consequently these
components can be adequately controlled before mixing.
Co-processed excipients are combinations of two or more
excipients that possess performance advantages that cannot be
achieved using a physical admixture of the same combination of
excipients. Typically they are
Journal of Advanced Pharmaceutical Sciences
Review Article eISSN 2249-5797
Abstract: There has been a radical change in tablet
manufacturing due to the introduction of processes such as direct
compression method and use of high-speed machines. Due to the
above-mentioned technologies, there has been an increased demand
for exploiting the diverse functionalities of excipients that makes
use of their flow and compression properties. Due to the simplicity
in terms of manufacturing and associated cost implied, direct
compression method is a highly preferable method of tablet
production. This in turn has lead to an increased research and
detailed study for developing newer excipients with better
tableting properties. Various techniques along with substantial
usage of particle engineering and material sciences have been
employed for the introduction of a new class of excipients called
as co processed excipients. This review article has been written
with the aim of giving detailed information about the sources of
new excipients, potential advantages of co-processed excipients,
material characteristics required for co-processing, various
methods of preparing co-processed excipients for direct compression
available in the market, description of some available co-processed
excipients, evaluation parameters for checking the functionality of
co-processed excipient and their future developments.
Keywords:
Direct compression, co-processing, new sources, and evaluation
parameters
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produced using some form of specialized manufacturing process.
The performance benefits relate to the manufacture or performance
of the finished pharmaceutical product. This improvement in
performance has been a primary drive for the introduction of
co-processed excipients into the marketplace. Co-processed
excipients are appropriate for consideration as new monographs
because one or more of the components may be formed in-situ, or the
component may not be isolated prior to co-processing. That is, the
manufacturing process for one component may not have been taken to
completion before the addition of the other components, and/or the
co-processed excipient combination cannot be adequately controlled
using the monograph tests for the individual component
excipients.(1)
There are many dosage forms in which co-processed excipients are
used mainly in solid dosage forms such as tablets, capsules,
powders, etc., liquid dosage forms such as emulsions, suspensions,
injections, etc., semi-solid dosage forms such as creams,
ointments, pastes, etc. As they have been used to enhance different
properties of dosage forms so, it finds application in nearly each
and every dosage form but mainly in solid dosage form.
Tablets are the most preferred dosage form of pharmaceutical
professionals because they can be accurately dosed and provide good
patient compliance. The ease of manufacturing, convenience in
administration, accurate dosing, and stability compared to oral
liquids, tamper-proofness compared to capsules, safe compared to
parental dosage forms makes it a popular and versatile dosage form
and can be produced at a relatively low cost. The development in
the field of APIs, excipients and tabletting machines during the
past decades has made tablet manufacturing a science. This
popularity of tablets coupled with an increased understanding of
the physics of compression and of manufacturing process variables
have matured the manufacture of tablets as a science in its own
right.
Since the introduction of tableting process in the early 1840s,
numerous changes have taken place, apart from changes in tablet
manufacturing, including the establishment of stringent regulatory
requirements for the materials that should be used, the
establishment of stability requirements, and the development of
high performance tabletting machines that can produce
100,000200,000 tablets/hour. Interestingly, such developments have
affected the manufacturing process negatively because the number of
materials that can fulfill such regulatory and performance
requirements has decreased substantially.(2)
Prior to the late 1950s, the literature contained few references
on the direct compression of pharmaceuticals. A great deal of
attention has been given to both product and process development in
the recent years. The availability of new materials, new forms of
old materials and the invention of new machinery has allowed the
production of tablets by simplified and reliable methods. In early
1960s, the introduction of spray dried lactose (1960) and Avicel
(1964) had changed the tablet manufacturing process and opened
avenues of direct compression tableting. Previously, the word
direct compression was used to identify the compression of a single
crystalline compound (i.e. sodium chloride, potassium chloride,
potassium bromide, etc.) into a compact form without the addition
of other substances.(3)
Shangraw conducted a survey in the United States of America in
which 58 products were surveyed to determine the most preferred
granulation process in which direct compression method was the most
accepted method. The results were in favour of direct compression.
Of the five processes listed in the survey, the average score (1.0
being the perfect score) for direct compression was 1.5 compared to
wet massing and fluid bed drying (2.0), wet massing and tray drying
(2.5), all in one (3.3) and roller compaction (3.6). About 41% of
the companies indicated that direct compression was the method of
choice, and 41.1% indicated that they used both direct compression
and wet granulation. Only 1.7% of
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the respondents indicated that they never used direct
compression and 15.5% indicated that the process was not
recommended.(4)
The direct compression process is highly influenced by powder
characteristics such flowability, compressibility, and dilution
potential. No single material is likely to exhibit all the ideal
characteristics. The physicomechanical properties of excipients
that ensure a robust and successful process are good flowability,
good compressibility, low or no moisture sensitivity, low lubricant
sensitivity, and good machining ability even in high speed
tableting machines with a reduced dwell time. Excipients with
improved functionality can be obtained by developing new chemical
excipients, new grades of existing materials and new combinations
of existing materials. New combinations of existing excipients are
an interesting option for improving excipient functionality because
all formulations contain multiple excipients. A much broader
platform for the manipulation of excipient functionality is
provided by co-processing. Co-processing is one of the most widely
studied options in the field of direct compression on order to
obtain functionality added excipients. In co-processing, two or
more excipients interact at the sub-particle level, the objective
of which is to provide a synergy of functionality improvement as
well as masking the undesirable properties of individual
components. A larger number of patented co-processed excipients are
available worldwide.(5)
Usually, a combination of plastic and brittle materials is used
for co-processing. This combination prevents storage of too much
elastic recovery during compression, which results in a small
amount of stress relaxation and a reduced tendency of capping and
lamination thereby resulting in optimum tableting performance.
Hence, co-processing these two kinds of materials produces a
synergistic effect in terms of compressibility by selectively
overcoming the disadvantages and helps improve functions, such as
the flow properties, compaction performance, strain rate
sensitivity, lubricant sensitivity or
sensitivity to moisture. One such material commercially
available internationally is Ludipress (BASF, USA), which contains
lactose (93.4%), povidone (3.2%), and crospovidone (3.4%).(5)
Tablets are manufactured primarily by either granulation
compression or direct compression. The latter involves the
compression of a dry blend of powders that contains drugs and
various types of excipients. The simplicity and cost effectiveness
of the direct-compression process have positioned direct
compression as an attractive alternative to traditional granulation
technologies. The demand of excipients with improved
functionalities, mainly in terms of flow and compression
properties, has increased with the advancement of tablet
manufacturing process. Co-processed excipients are a mixture of two
or more existing excipients at sub particle level, offer
substantial benefits of the incorporated excipients and minimize
their drawbacks. These multipurpose excipients have significantly
reduced the number of incorporating excipients in the tablet. The
present review discusses the development and source of new
excipients, potential advantages of co-processed excipients,
material characteristics required for co-processing, methods of
preparing directly compressible adjuvants and various co-processed
excipients for direct compression available in the market.(2)
Because many co-processed excipients contain a macromolecular
excipient as one of the constituents, responsibility for reviewing
these monographs and recommending them for inclusion in NF falls
within the purview of the EM2 Expert Committee, one of three Expert
Committees that set excipient standards for NF in USPs Council of
Experts. Recently there has been increased interest in NF
monographs for co-processed excipients. The Expert Committee is
therefore addressing the more general question of compendial
acceptance of these types of excipients. To this end the EM2 Expert
Committee believes that guidelines for the
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acceptance of monograph proposals for co-processed excipients
would be useful.(1) Advantages of co-processing(2)&(6) Improved
Flow Properties -
Controlled optimal particle size and particle- size distribution
ensures superior flow properties of co-processed excipients without
the need to add glidants. Improved compressibility
Co-processed excipients have been used mainly in direct
compression tabletting because in this process there is a net
increase in the flow properties and compressibility profiles and
the excipient formed is a fillerbinder.(2) Better dilution
potential
Dilution potential is the ability of the excipient to retain its
compressibility even when diluted with another material. Most
active drug substances are poorly compressible, and as a result,
excipients must have better compressibility properties to retain
good compaction even when diluted with a poorly compressible
agent.(6) Fill weight variation
In general, materials for direct compression tend to show high
fill weight
variations as a result of poor flow properties, but co processed
excipients, when compared with simple mixtures or parent materials,
have been shown to have fewer fill weight variation problems. The
primary reason for this phenomenon is the impregnation of one
particle into the matrix of another, which reduces the rough
particle surfaces and creates a near optimal size distribution,
causing better flow properties. Fill weight variation tends to be
more prominent with high-speed compression machines.(2) Reduced
lubricant sensitivity
Most co processed products consist of a relatively large amount
of brittle material such as lactose monohydrate and a smaller
amount of plastic material such as cellulose that is fixed between
or on the particles of the brittle material. The plastic material
provides good bonding properties because it creates a continuous
matrix with a large surface for bonding. The large amount of
brittle material provides low lubricant sensitivity because it
prevents the formation of a coherent lubricant network by forming
newly exposed surfaces upon compression, thus breaking up the
lubricant network.(2)
Table 1: Co processed directly compressible excipients.(2)
Co-processed excipients
Trade name Manufacturer Added advantage
Lactose, 3.2% kallidon 30,
kallidon CL Ludipress Basfag, ludwigshafen, germany
Low degree of hygroscopicity, good flowability, tablet hardness
independent of machine speed
Lactose, 25% cellulose Cellactose
Meggle gmbh & co. Kg, germany
Highly compressible, good mouth feel, better tableting at low
cost
Sucrose 3% dextrin Dipac Penwest pharm. company Directly
compressible
Microcrystalline cellulose, Silicon dioxide Prosolv
Penwest pharmaceuticals
company
Better flow, reduced sensitivity to wet granulation, better
hardness of tablet, reduced friability
Microcrystalline cellulose, Guar gum Avicel ce-15 Fmc
corporation Less grittiness, minimal chalkiness, overall
palatability
Calcium carbonate, Sorbitol Formaxx Merck Controlled particle
size distribution
Microcrystalline cellulose, Lactose Microlela Meggle
Capable of formulating high dose, small tablets with poorly
flowable active ingredients
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Need of co-processed excipients The excipients industry to date
has been an
extension of the food industry. Moreover, excipients are
products of the food industry, which has helped maintain a good
safety profile. Increasing regulatory pressure on purity, safety,
and standardization of the excipients has catalyzed the formation
of an international body, the International Pharmaceutical
Excipients Council (IPEC). IPEC is a tripartite council with
representation from the United States, Europe, and Japan and has
made efforts to harmonize requirements for purity and functionality
testing. The development of new excipients to date has been market
driven (i.e., excipients are developed in response to market
demand) rather than marketing driven (i.e., excipients are
developed first and market demand is created through marketing
strategies) and has not seen much activity as shown by the fact
that, for the past many years, not a single new chemical excipient
has been introduced into the market. The primary reason for this
lack of new chemical excipients is the relatively high cost
involved in excipients discovery and development. However, with the
increasing number of new drug moieties with varying physicochemical
and stability properties, there is growing pressure on formulators
to search for new excipients to achieve the desired set of
functionalities.(7) Other factors driving the search for new
excipients are
The growing popularity of the direct- compression process and a
demand for an ideal fillerbinder that can substitute two or more
excipients
Tableting machinerys increasing speed capabilities, which
require excipients to maintain good compressibility and low weight
variation even at short dwell times.
Shortcomings of existing excipients such as loss of compaction
of microcrystalline cellulose (MCC) upon wet granulation,
high moisture sensitivity, and poor die filling as a result of
agglomeration.
The lack of excipients that address the needs of a specific
patient such as those with diabetes, hypertension, and lactose and
sorbitol sensitivity.
The ability to modulate the solubility, permeability, or
stability of drug molecules.
The growing performance expectations of excipients to address
issues such as disintegration, dissolution, and bioavailability.(7)
Sources of new excipients
Excipients with improved functionality can be obtained by
developing new chemical excipients, new grades of existing
materials, and new combinations of existing materials. Any new
chemical excipient being developed as an excipient must undergo
various stages of regulatory approval aimed at addressing issues of
safety and toxicity, which is a lengthy and costly process. In
addition, the excipient must undergo a phase of generic
development, which shortens the market exclusivity period. The high
risk and significant investment involved are not justified in view
of the meager returns from the new excipients. A plausible solution
is for excipient and pharmaceutical manufacturers to develop drug
products jointly, during which a new excipient becomes part and
parcel of the eventual new drug application. This type of
arrangement already has been successfully applied in the
intravenous delivery field, in which Cy Dex and Pfizer worked
collaboratively to obtain the approval of a solubilizer.(2)
The combined expertise of pharmaceutical and excipient companies
can lead to the development of tailor made innovative excipients.
Developing new grades of existing excipients has been the most
successful strategy for the development of new excipients in past
three decades, a process that has been supported by the
introduction of better performance grades of excipients such as
pregelatinized starch, croscarmellose, and crospovidone.
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Fig 1: Comparative developmental time lines for a drug product
and a new chemical excipient.(8)
However, functionality can be improved only to a certain extent
because of the limited range of possible modifications. A new
combination of existing excipients is an interesting option for
improving excipient functionality because all formulations contain
multiple excipients. Many possible combinations of existing
excipients can be used to achieve the desired set of performance
characteristics. However, the development of such combinations is a
complex process because one excipient may interfere with the
existing functionality of another excipient. Over the years, the
development of single- bodied excipient combinations at a sub
particle level, called co processed excipients, has gained
importance. New physical grades of existing excipients and co
processed excipients are discussed further in the following section
of this article that explains particle engineering. Particle
engineering is a broad- based concept that involves the
manipulation of particle parameters such as shape, size, size
distribution, and simultaneous minor changes that occur at the
molecular level such as polytypic and polymorphic changes. All
these parameters are translated into bulk level changes such as
flow
properties, compressibility, moisture sensitivity, and
machinability. 3.1 Particle engineering as source of new excipients
Solid substances are characterized by three levels of solid state:
the molecular, particle, and bulk level. These levels are closely
linked to one another, with the changes in one level reflecting in
another level. The molecular level comprises the arrangement of
individual molecules in the crystal lattice and includes phenomena
such as polymorphism, pseudopolymorphism, and the amorphous state.
Particle level comprises individual particle properties such as
shape, size, surface area, and porosity. The bulk level is composed
of an ensemble of particles and properties such as flowability,
compressibility, and dilution potential, which are critical factors
in the performance of excipients. The fundamental solid state
properties of the particles such as morphology, particle size,
shape, surface area, porosity, and density influence excipient
functionalities such as flowability, compactability, dilution
potential, disintegration potential, and lubricating potential.
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Fig 2: Three levels of solid state.(8)
Hence, the creation of a new excipient must begin with a
particle design that is suited to deliver the desired
functionalities. Varying the crystal lattice arrangement by playing
with parameters such as the conditions of crystallization and
drying can create particles with different parameters. It is also
possible to engineer particles without affecting the proceeding
molecular level. Avicel 101 and 102 (microcrystalline cellulose)
and spray dried lactose are examples in which such an approach has
been successfully applied. However, particle engineering of a
single excipient can provide only a limited quantum of
functionality improvement.(2)
A much broader platform for the manipulation of excipient
functionality is provided by co-processing or particle engineering
two or more existing excipients. Co-processing is based on the
novel concept of two or more excipients interacting at the sub
particle level, the objective of which is to provide a synergy of
functionality improvements as well as masking the undesirable
properties of individual excipients. The availability of a large
number of
excipients for co-processing ensures numerous possibilities to
produce tailor made designer excipients to address specific
functionality requirements. Co-processed excipients are prepared by
incorporating one excipient into the particle structure of another
excipient using processes such as co-drying. Thus, they are simple
physical mixtures of two or more existing excipients mixed at the
particle level. Co-processing was initially used by the food
industry to improve stability, wettability, and solubility and to
enhance the gelling properties of food ingredients such as co
processed glucomannan and galactomannan.(2) Co-processing of
Excipients in the pharmaceutical industry can be dated back to the
late 1980s with the introduction of co processed microcrystalline
cellulose and calcium carbonate, followed by Cellactose (Meggle
Corp.,Wasserburg, Germany) in 1990, which is a co processed
combination of cellulose and lactose. A similar principle was
applied in developing silicified microcrystalline cellulose (SMCC),
which is the most widely used co processed excipient. Co-processing
excipients leads to the formation of excipient granulates with
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superior properties compared with physical mixtures of
components or with individual components. They have been developed
primarily to address the issues of flowability, compressibility,
and disintegration potential, with fillerbinder combinations being
the most commonly tried. The combination of excipients chosen
should complement each other to mask the undesirable properties of
individual excipients and, at the same time, retain or improve the
desired properties of excipients. For example, if a substance used
as a fillerbinder has a low disintegration property, it can be
co-processed with another excipient that has good wetting
properties and high porosity because these attributes will
increase the water intake, which will aid and increase the
disintegration of the tablets.(2) Technologies used in preparation
of co processed excipients Roller compaction
Dry granulation process is a particle-bonding process. Miller
described the theory of granule bond formation as:
a. Particle rearrangement b. Particle deformation c. Particle
fragmentation d. Particle bonding.
Fig 3: Co-processing methodology.(8)
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In the roller compaction process, powder blends first pass a
feeding zone, where most of the rearrangement occurs. The dense
powders then go through a compaction zone, where increasing force
is being exerted by two counter-rotating rolls. As the pressure
goes up further into the compaction zone, the particles deform,
fragment, and bond to form ribbons. Roller compaction is widely
applied to dry granulation. It offers many superior
characteristics, e.g., good control of process and cost-advantages
compared to wet granulation. As no liquid or drying is involved,
this process is more suitable for water or heat-sensitive drugs.(9)
Compared to direct compression, roller compaction can handle high
drug loading, improve flow and content uniformity, and prevent
segregation. Like any other processes, dry granulation has its own
issues, such as loss of compactibility or dissolution problem. A
systematic approach of formulation and process development is the
key to high quality drug products. Fig. 4 outlines a brief flow
chart for formulation and process development using roller
compaction. At high drug loading, the compactibility and
flowability of drug substance will be critical for roller
compaction and tableting processes.(10) Different excipients need
to be evaluated in formulation development to achieve desirable
chemical stability, tablet properties, and process control. After
selecting a suitable roller compactor, potential critical process
parameters and material attributes can be identified using a risk
management strategy. The fishbone diagram and Failure Mode and
Effects Analysis (FMEA) are useful tools for risk management.
Design of experiment (DOE) can be used to identify the critical
quality attributes and design space for the overall
process.(11)&( 12) Wet granulation
Wet granulation is a process still widely used in the
pharmaceutical industry. It has not been replaced by direct
compression technology, partly because of development cost
considerations and habits, and partly because it remains in some
cases an attractive technique.
Fig 4: A brief flow chart for formulation and process
development using roller
compaction.(11) It provides better control of drug content
uniformity at low drug concentrations, as well as control of
product bulk density and ultimately compactibility (brittle
fracture), even for high drug contents.
Processing takes place in one of two types of closed granulating
systems: fluid bed granulators or high-shear mixers. The two
techniques differ technically on the mode of solid agitation, and
fundamentally on the mode of granule growth. In fluid bed
granulation, the powder mix is maintained as a fluidized bed by a
flow of air injected upwards through the bottom screen of the
granulator. The binding solution is sprayed above the powder bed,
in a direction opposite to the air flow. Other spraying directions
can be used on the same equipment for solids coating. The granules
result from the adhesion of solid particles to the liquid droplets
that hit the bed. Partial drying by the fluidizing air occurs
continuously during granulation. The process continues until all
the powder has been
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agglomerated, and it needs to be stabilized as far as moisture
balance is concerned. The equilibrium may not be constant, however,
as the moisture content of the granules could be increasing
slightly throughout the process, and the trajectories of the
particles may change with changes in the density of the
agglomerated powder bed. Complete drying is quickly achieved in the
hot air stream when binder spraying is stopped.(13)
In high-shear granulation, an impeller maintains the powder in
agitation in a closed vessel, and here also a binder solution is
sprayed from the top. As the liquid droplets disperse in the
powder, they form the first nuclei of future granules. The
agitation forces prevent the development of large agglomerates,
because they would be too fragile to sustain the shear. However, as
mixing and spraying proceed, the existing agglomerates undergo
densification, whereby the internalized binder is squeezed out to
the surface of the wet agglomerates. This has two consequences. It
makes the agglomerates harder, and their surface more adhesive, and
hence granule growth enters a new, more efficient phase. The
process is stopped somewhere in this phase before an excess of
liquid or excessive densification provokes a phase inversion, i.e.
a slurry or uncontrollable growth (balling phenomenon). The drying
step traditionally takes place after transferring the damp mass
into another piece of equipment (fluid bed dryer), but the use of
single-pot technology (drying in place) is now spreading. The
granules formed are understandably denser than those obtained in
fluid bed granulation.(14)
By definition, process scale-up is the transfer of a controlled
process from one scale to another. It implies that the process on
the small scale is understood and controlled, and ideally that some
basic rules can be followed to quickly obtain optimization and
control of the process at the bigger scale.(15) The above figure is
the flow chart of how a general process of wet granulation occurs
at industrial level.
Fig 5: Flow chart of wet granulation (16)
Hot melt extrusion (HME) Hot melt extrusion is another
thermal
processing technique that has attached interest as a novel
approach for the development of polymeric immediate, sustained
release or transdermal/transmucosal delivery system. This process
is widely used in transferring and melting of polymer inside a
barrel by a rotating screw. The polymer melt is then pressurized
through the die and solidify into variety of shapes. Extrusion can
be further processed into tablets or granules. HME is a continuous,
simple and efficient process. No water or no solvent is required as
the molten polymer can function as a thermal binder. The intense
mixing and agitation during HME also deaggregates particles and
improves the content uniformity of the extrudates. HME requires
high temperature greater than 80C. The excipient and the active
ingredient need to be stable under those conditions. Plasticizers,
antioxidants and other excipients can be included into the power
blend to improve the processing condition and stability of each
component during extrusion.(17) Spray drying-
This technique enables the transformation of feed from a fluid
state into dried particulate form by spraying the feed into a hot
drying medium. It is a continuous particle processing drying
operation. The feed can be a solution, suspension, dispersion or
emulsion. The dried product can be in the form of powders, granules
or agglomerates depending upon the physical and chemical properties
of the feed, the dryer design and final powder properties
desired.(18)
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Spray drying process mainly involves five steps:
i. Concentration: feedstock is normally concentrated prior to
introduction into the spray dryer.
ii. Atomization: the atomization stage creates the optimum
condition for evaporation to a dried product having the desired
characteristics.
iii. Droplet-air contact: in the chamber, atomized liquid is
brought into contact with hot gas, resulting in the evaporation of
95%+ of the water contained in the droplets in a matter of a few
seconds.
iv. Droplet drying: moisture evaporation takes place in two
stages- 1) during the first stage, there is sufficient moisture in
the drop to replace the liquid evaporated at the surface and
evaporation takes place at a relatively constant rate. The second
stage begins when there is no longer enough moisture to maintain
saturated conditions at the droplet surface, causing a dried shell
to form at the surface. Evaporation then depends on the diffusion
of moisture through the shell, which is increasing in
thickness.
v. Separation: cyclones, bag filters, and electrostatic
precipitators may be used for the final separation stage. Wet
Scrubbers are often used to purify and cool the air so that it can
be released to atmosphere. Spray drying process (Figure V )
have
advantages that can be designed to virtually any capacity
required. Feed rates range from a few pounds per hour to over 100
tons per hour. Operation is continuous and adaptable to full
automatic control. It can be used with both heat-resistant and heat
sensitive products. Nearly spherical particles can be produced.
There are some limitation that includes limited versatility in
producing particles or structures with the complex morphologies,
and rapid drug release rates often exhibiting a burst
effect.(19)
Figure V : Spray drying.(19)
Some examples of coprocessed excipients Ludipress -
Ludipress, a co-processed product, consists of 93.4% a-lactose
monohydrate, 3.2% polyvinyl pyrrolidone (Kollidon 30) and 3.4%
crospovidone (Kollidon CL). It consists of lactose powder coated
with polyvinyl pyrrolidone and crospovidone. Although, Ludipress
contains disintegrant, the disintegration of tablets takes longer
than tablets containing a-lactose monohydrate, Tablettose and
anhydrous -lactose.(20) At low compression force Ludipress gives
harder tablets but the addition of glidant and disintegrant is
needed. It is reported that binding capacity of Ludipress was
higher than that of microcrystalline cellulose. The dilution
potential was high (upto 70%) when aspirin was used a model
drug.(21) Baykara et al. reported that the dilution potential of
LudipressR with paracetamol is lower than that of Avicel PH-101,
Elcema G250 and Elcema P050. The binding properties of Ludipress,
both unlubricated and lubricated with 1% magnesium stearate was
found to be much better than corresponding physical mixture.(22)
Plaizier-Vercammen et al. reported that the addition of a lubricant
was necessary and its mixing time had little effect on crushing
strength of Ludipress tablets. Authors also reported that Ludipress
exhibits better tableting characteristics for low dose APIs, and
good batch-to-batch
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uniformity than Cellactose.(23) The compressibility of Ludipress
is similar to that of Avicel PH-200. The disintegration time of
Ludipress containing tablets remained unchanged at about 100 MPa
compaction pressure while significant prolongation was observed
with Cellactose.(24) Schmidt and Rubensdorfer reported that the
tablets manufactured with Ludipress exhibited optimum
disintegration time and compaction pressure independent dissolution
of glibenclamide. While, increasing compaction pressure had a
negative effect on drug dissolution from compacts containing
Cellactose.(25) It has been reported that among various lactose
based directly compressible excipients, Ludipress exhibited a
better flow rate compared to Avicel PH 101. Ludipress exhibited
highest flowability followed by Cellactose, Tablettose, Fast Flo
lactose and anhydrous lactose as demonstrated by lower static and
dynamic angles of repose than the other excipients.(26) The values
of compressibility could be ranked from maximum to minimum in the
following order: Tablettose, Cellactose, Ludipress and Fast Flo
lactose. Fragmentation propensity was from maximum to minimum in
Tablettose, Cellactose, Ludipress and Fast-Flo lactose.(27)
Cellactose -
Cellactose is a co-processed product consisting a-lactose
monohydrate (75%) and cellulose (25%). Apart from good flowability,
it has good compactibility. The compactibility is attributed to a
synergetic effect of consolidation by fragmentation of lactose and
plastic deformation of cellulose.(28) Because the lactose covers
the cellulose fibers, moisture sorption is much lower than that of
microcrystalline cellulose alone.
Aufmuth et al reported that the Cellactose exhibited increased
crushing strength of the compacts along with reduced friability and
lower disintegration time than the dry blend of lactose and
cellulose. Armstrong et al. pointed that Cellactose exhibit the
dual consolidation behaviour since it contains a fragmenting
component (lactose) and a substance that
consolidates primarily by plastic deformation
(Cellulose).(29)
Ruiz et al. and Reimerdes found that the Cellactose exhibited
better compressibility compared to Ludipress, Fast Flo lactose,
Tablettose, Di-pac and anhydrous lactose.(30) Belda and Mielck
found that due to co-processing Cellactose exhibited enhanced
crushing strength compared to the powder mixtures each containing
25% w/w Avicel PH-101 or Elcema P-100 and 75% w/w Tablettose or
lactose (100#).(31) Casalderrey et al reported that the Cellactose
tablets prepared at a compression pressure that largely eliminated
macro pores had better mechanical properties but much poorer
disintegration than tablets of the other blends having similar
composition, particle size, and true density at the same punch
pressure. Authors further reported that the tensile strength and
disintegration time of Cellactose tablets decreased rapidly as the
compression pressure is reduced.(31) Gohel and Jogani(32) prepared
and evaluated co-processed directly compressible adjuvant
containing lactose and microcrystalline cellulose using starch as a
binder. The percentage fines, Carrs index of the agglomerates as
well as friability and tensile strength of the tablets were
affected by the ratio of lactose to microcrystalline cellulose and
percentage of starch in binder solution. A product containing
lactose: microcrystalline cellulose (9:1) and 1% starch paste
exhibited satisfactory flow, compressibility and friability.
Tablets of diltiazem hydrochloride and acetaminophen prepared using
the co-processed excipients exhibited satisfactory tableting
properties.(32) Gohel et al. prepared and evaluated coprocessed
diluents containing lactose and microcrystalline cellulose using a
23 factorial design. Ratio of lactose to MCC (75: 25 and 85:15),
type of binder (hydroxypropyl methylcellulose or dextrin) and
binder concentration (1 or 1.5%) were studied as independent
variables.(33) The results revealed that the lactose:
microcrystalline cellulose ratio 75:25 and dextrin as a binder are
better than the ratio of 85:15 and hydroxypropyl methylcellulose as
a
AsusHighlight
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binder. The tableting properties of the developed adjuvant were
ascertained using diltiazem HCl as a model drug.(33) Gohel and
Jogani prepared co-processed directly compressible adjuvant
containing lactose and microcrystalline cellulose using melt
granulation technique. Gohel et al. demonstrated use of factorial
design in development of directly compressible adjuvant of desired
characteristics consisting of lactose, dicalcium phosphate and
microcrystalline cellulose.(34) Pharmatose DCL 40 - It is a
co-processed product consisting of 95% -lactose and 5% anhydrous
lactitol. Due to spherical shape and favourable particle size, it
exhibits good flowability. It has high dilution potential than
other lactose based products due to better binding property. It has
very low water uptake at high humidity.(35) Prosolv
It is co-processed silicified microcrystalline cellulose. It
consists of 98% microcrystalline cellulose and 2% colloidal
silicone dioxide. The manufacturer claim better flowability and
compressibility compared to Emcocel and Avicel PH 101 or physical
mixture of MCC with colloidal silicone dioxide. Allen reported that
Prosolv containing tablets were significantly robust than those
produced from regular cellulose by wet granulation. In the presence
of magnesium stearate (0.5 %), tablets prepared with Prosolv
maintained tensile strength profiles, whereas the tensile strength
of regular cellulose was significantly affected. Author further
reported that Prosolv is about 20% more compactable than regular
cellulose. Fraser et al reported that silicified microcrystalline
cellulose has some improvement in flow but considerably enhanced
mechanical properties. Lahdenpaa et al. demonstrated that
Silicified microcrystalline cellulose is useful to prepare tablet
containing poorly compressible ingredients by direct
compression.(36) The silicification affects the moisture sorption
and the packing during tapping as well as the particle deformation
during tableting. Prosolv showed slight increase in the
tensile strength but marked increase in the disintegration time
of the tablets compared to Avicel. Bolhuis et al. demonstrated that
the co-processing of microcrystalline cellulose with colloidal
silicone dioxide has no significant contribution on the tablet
strength of lubricated tablets containing the physical mixture of
microcrystalline cellulose and colloidal silicone dioxide.(37)
StarLac
Starlac is a co-processed excipient consists of lactose
monohydrate and maize starch produced by spray drying. The
advantage of Starlac are its good flowability depending on the
spray-drying process, an acceptable crushing force due to its
lactose content, its rapid disintegration depending on starch.
Gohel and Jogani demonstrated use of multiple linear regressions in
development of co-processed lactose and starch. Authors concluded
that as the lactose/starch ratio increased Carrs index of the
adjuvant and crushing strength of the tablets increased while
friability decreased. Percentage of starch paste has inverse effect
on the friability.(32) Microcrystalline cellulose (MCCII) -
Microcrystalline cellulose (MCCII) was recently introduced as a
new filler/binder for solid dosage forms, and has been recommended
as a suitable excipient when a rapidly disintegrating compact is
desirable. However, the main shortcoming of this excipient is its
low compactibility and its fibrous shape, which limit its
application to formulate poorly compactable and poorly flowing
drugs. Traditionally, excipient functionality has been economically
accomplished by engineering particles physically. New grades of
existing excipients have been created by modifying the fundamental
properties of materials, including their morphology, particle size,
shape, surface area, porosity and density. These modifications can
result in improved derived properties such as flowability,
compressibility, compactibility, dilution, disintegration and
lubrication potentials.(1)&(38) However, if one attribute is
improved, another could be compromised. For example, Avicel
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products have been engineered in different size grades such as
Avicel PH200, which has excellent flow properties but a poor
compactibility. Conversely, Avicel PH101 has poor flow properties,
but excellent compactibility.(39) One of the most successful
approaches used in recent years for particle engineering is
co-processing two or three excipients together. In this technique,
excipients interact at the particle level, enhancing functionality
as well as masking the undesirable properties of the individual
components. The resulting excipient has superior properties
compared to the physical blending of the individual components.
Excipients that are physically modified in this fashion do not lose
their chemical structure and stability, and they maintain their
independent chemical properties. Particles of one material can be
incorporated onto the companion material by spray-drying, wet
granulation, spheronization, co-milling, co-crystallization, and
other techniques. Amorphous SiO2 has been widely used as a flow
enhancer in powder formulations for food and pharmaceutical
applications. Recently, it has been used as a companion excipient
for co-processing with starch (10:1), chitin (1:1), or cellulose I
(98:2) resulting in products with improved unique characteristics
different from the parent materials. For example starch:SiO2
compacts disintegrate rapidly, often within 30s. Chitin:SiO2
powders have increased bulk density and good flow properties.
Likewise, cellulose I:SiO2 products have excellent compaction
properties, show less sticking to the lower punches and have
superior dissolution stability over the physical mixture of MCCI
and SiO2. Further, calorimetric and water sorption studies
determined a surface heterogeneity for SMCCI. For all the above
reasons, coprocessing materials are gaining wider acceptance. After
conducting preliminary screening studies using several coprocessing
companion materials and different techniques, SiO2 along with spray
drying was the only combination that improved the mechanical
properties of MCCII without
detriment of its self-disintegrating characteristics.(40)
Directly compressible sucrose -
Sucrose is one of the oldest ingredients used by the food and
pharmaceutical industries. This natural product has been around for
thousands of years and has enjoyed immense popularity because of
its pleasant sweet taste. It has been used in a wide range of
applications, mostly because of its ability to mask the bitter
taste of other ingredients with its sweetness. In the
pharmaceutical arena, taste masking is a particularly attractive
benefit of using sucrose. Unfortunately sucrose in its natural
state does not compress well and various crystallization techniques
have been employed to make it compressible. Granulating sucrose
with a small percentage of another ingredient has been successful
in producing directly compressible sugars. There are many types of
compressible sugars available today and most of them are sucrose
granulated with a small percentage of modified dextrins in order to
make the sucrose compressible. Recently, a new directly
compressible sucrose has been introduced onto the market that shows
some benefits over existing products. It is made by a unique
crystallization process in which 95% sucrose and 5% sorbitol are
combined. The result is a highly compressible sugar excipient for
tableting applications.(41) Di-Pac-
Di-Pac is a directly compressible, co-crystallized sugar
consisting of 97% sucrose and 3% modified dextrin. It is a free
flowing, agglomerated product consisting of hundreds of small
sucrose crystals glued together by the highly modified dextrin. At
high moisture level, Di-pac begins to cake and loose its fluidity.
Tablets containing a high proportion of Di-pac tend to harden after
compression at higher relative humidity. Its sweet taste makes it
suitable for most directly compressible chewable tablets. Rizzuto
et al., demonstrated that co-crystallized sucrose and dextrin
deformed readily by plastic fracture to provide much harder
compacts than those obtained from sucrose crystals alone.(42)
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Starch 1500- It is a directly compressible, free flowing,
USP grade of partially hydrolyzed cornstarch. It is prepared by
subjecting cornstarch to physical compression or shear stress in
high moisture conditions causing an increase in temperature and a
partial gelatinization of some of the starch granules. The product
is consists of about 5% free amylose, 15% amylopectin and 80%
unmodified starch. It provides fair to good binding properties and
dilution potential, but requires high pressures to produce hard
tablets. It also produces a dense tablet with good disintegration
properties. Starch 1500 exhibits self-lubricating property. It has
poor flowability compared to other directly compressible adjuvants
and shows higher lubricant sensitivity. It is also used as filler
in capsule formulation. Monedero Perales et al.(44) demonstrated
that Starch 1500 exhibited better flowability and lower binding
property and plasticity than the Sepistab 200. Terfenadine tablets
prepared using rice starch (Era Tab) exhibited higher crushing
strength and lower friability than partially pregelatinized starch,
Super-Tab, Emcompress and lower than Avicel PH 101. Uni-Pure is a
fully gelatinized maize starch. It gives tablets with strong
binding properties and significantly faster disintegration. Clausen
reported co-processed polymethacrylic acid-starch as a pH-sensitive
directly compressible excipient for controlled delivery of model
drugs amoxicillin and rifampicin.(43)&(44) Evaluation
parameters for co processed excipients Particle size distribution-
The particle size distribution can be calculated by statistical
method such as frequency curve method. When the number, or weight,
of particles lying within a certain size range is plotted against
the size range or mean particle size, a so called frequency curve
is obtained.(45) Carrs index-
The bulk density is the quotient of the weight to the volume of
sample. The tapped density was determined as the quotient of the
weight of the sample to the volume after tapping a measuring
cylinder 500 times from a height of 2
inches. Carrs index (percentage compressibility) was calculated
as one hundred times the ratio of the difference between the tapped
density and bulk density to the tapped density.(46)
Hausner Ratio- Hausner ratio is the ratio of bulk density to the
tapped density.(46)
Angle of repose- The angle of repose is a relatively simple
technique for estimating the flow properties of a powder. It can
easily be determined by allowing a powder to flow through a funnel
and fall freely onto a surface. The height and diameter of the
resulting cone are measured and the angle of repose calculated from
this equation:
Where, h is the height of the powder cone and r is the radius of
the powder cone.(16)
Case studies Gohel and Jogani prepared co-processed
directly compressible adjuvant containing lactose and
microcrystalline cellulose using melt granulation technique. Gohel
et al. demonstrated use of factorial design in development of
directly compressible adjuvant of desired characteristics
consisting of lactose, dicalcium phosphate and microcrystalline
cellulose.(34)
Stoltenberg et al., Breitkreutz et al., (2011) carried out study
of development of orally disintegrating mini tablets (ODMTs) as a
suitable dosage form for paediatric patients. The suitability of
five commercially available ready-to-use tableting excipients,
Ludiflash_, Parteck _ ODT, Pearlitol_ Flash, Pharmaburst_ 500 and
Prosolv_ ODT, to be directly compressed into minitablets, with 2 mm
in diameter, was examined. All of the excipients are based on
co-processed mannitol. The use of coprocessed excipient was found
to be improving ODMTs properties such as crush strength and
friability.(47)
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Olowosulu1 et al, Oyi1 et al, Isah1 et al, Ibrahim et al (2011)
have developed an efficient direct compression tabletting excipient
of coprocessed particles of maize starch (MS) and acacia gum (Ac)
by co-drying their well dispersed aqueous mixtures.(48)
Gonnissen et al., Remon et al., Vervaet et al.,(2007) have
developed a technique of Continuous production of directly
compressible powders by coprocessing acetaminophen and
carbohydrates via spray drying.(49) Future trends
The obvious advantages of solid dosage forms and changing
technological requirements will keep alive the search for newer
excipients. The newer excipients are required to be compatible not
only with the latest technologies and production machineries, but
also with the innovative active principles such as those
originating from biotechnology. Developments in the field of
excipients and manufacturing machinery have helped in establishing
traditional inert excipients as functional components. A deeper
understanding of their solid-state properties and its impact on
excipient functionality is further going to fuel this trend.
Functionalities, hitherto unavailable to the formulator, can now be
incorporated into the product by judicious choice of
high-functionality excipients. Further, a narrow pipeline of new
chemical excipients, and an increasing preference for the direct
compaction process, creates a significant opportunity for the
development of high-functionality excipients. A greater synergy
between excipient manufacturers and the pharmaceutical manufacturer
in the future is going to help in the development of tailor-made
designer excipients complying with safety, performance, and
regulatory issues. Conclusions
Technological advancements in tablet manufacturing, introduction
of high-speed machineries, and a shift in tableting toward direct
compaction have catalyzed the search for newer excipients meeting
these requirements. Excipients are no more considered as inert
ingredients of a
formulation, but have a well-defined functional role.
Developments in particle engineering have provided wide avenues for
designing excipients with predefined functionality requirements.
Coprocessed excipients are a result of this arduous innovation
only, wherein two excipients are coprocessed to provide products
with improved functionality by retaining their favorable and
avoiding the unfavorable properties. A better appreciation of this
concept can be viewed from the vast number of coprocessed
excipients available in the market. The success of these excipients
depends on their quality, safety, and functionality. Although the
first two parameters have remained constant, significant
improvements in functionality provide wide opportunities for the
increased use of coprocessed excipients. The advantages of these
excipients are numerous, but further scientific exploration is
required to understand the mechanisms underlying their performance.
The main obstacle in the success of coprocessed excipients is the
noninclusion of their monographs in official pharmacopeias, which
discourages their use by pharmaceutical manufacturers. With
recommendations from IPEC and the continual efforts of excipient
manufacturers, these products could find their way into official
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