3XQ`dUb"

" 9>DB?4E3D9?>
"! 9^db_TeSdY_^

In this chapter we explain the targets or goals of this research. We explain

what properties the product developed in this thesis should have to meet these
goals. Furthermore, a literature review is presented that describes existing
products with properties similar to the ones described in this thesis.

"" 2QS[Wb_e^T

The term detergents used in this thesis applies only to those products
used for fabric cleaning and not for personal use or cleaning other media.
Furthermore, the product developed is for use in a dry powder detergent, the
detergent consists of granulated components and has the form of a dry powder
prior to use.
Most powder detergents consist of 5 classes of components:
1. Surfactants, i.e. surface active components,
2. builders, for removal of calcium and magnesium ions from the washing
water,
3. bleach systems, for removal of organic colors of fabrics,
4. enzymes, which catalyze biochemical reactions,
5. minors, such as perfume and anti-foam components.
The surfactants perform two functions. The first is the lowering of the
surface tension to enhance the removal of fatty material from the fabrics. The
second is the formation of micelles which act as reservoirs for the removed fatty
material by solubilizing it.
Calcium and magnesium ions are impurities present in the washing water
which cause precipitation of anionic and soap detergents. This causes a decrease
in the efficiency of the surfactants and the unwanted effect of precipitates on
clothing. To remove the calcium and magnesium ions builders are used. This is
done by precipitation (precipitative builders, e.g. sodium carbonate), complex
forming (e.g. sodiumtripolyphosphate) and by ion-exchange with the aid of
zeolites.
Bleaches are used to remove organic colors from fabrics. The color of the
stains is often derived from a complicated organic molecule having a variety of

%
9^db_TeSdY_^

reactive or unsaturated groups and bonds. The oxidizing agent attacks these
molecules and oxidizes them to less complicated molecules that are commonly
colorless.
Enzymes are used to breakdown complex biomolecules, the following
types are most common in detergents:
- amylases, for the breakdown of starches (potato, pasta),
- proteases, for the breakdown proteins (blood, gravy, milk),
- lipases, for the breakdown of fats,
- cellulases, for fabric improvement.
Minor components in a detergent are perfume, optical brighteners, anti-
rediposition agents and anti-foam agents.
In the existing powder detergents all these components are dissolved
simultaneously in the washing water. However, since some of the components
are not compatible with each other, sequential release of the components in the
washing water could potentially make more efficient use of these components
compared to simultaneous action.

"# DQbWUdcW_Q\c
"#!9^SbUQcUT `UbV_b]Q^SU Ri S_^db_\\Y^W dXU bU\UQcU `b_VY\U _V Q
TUdUbWU^d
Increasing the washing performance by sequential release of the
components or the incorporation of several washing stages is not a new idea.
Already in 1960 a two phase washing stage was described in a patent [US
3,042,621]. The general idea of this patent is that a detergent contains many
components, some of which are not compatible to an extent that they deactivate
each other. To solve this problem the individual components are dosed
sequentially to the washing water, so preventing interaction between different
components.
Ideally, this principle of sequential dosing should be implemented in the
powder detergent as an additional function of the product. This is the main goal
of the products developed in this thesis: the development of a powder
formulation that can dose detergent components sequentially to the washing
water.

"#"9^SbUQcUTcdQRY\Ydi_VTUdUbWU^dS_]`_^U^dcTebY^Wcd_bQWU
Stability is an important issue in detergents. Detergents contain very
mobile components even in a dry state (non-ionic surfactants) and can take up
water during storage. This can cause problems due to the deactivation of several

&
  3XQ`dUb"


components. Products that are likely to have a positive effect on the stability
(i.e. formulations that have a protective barrier for active components) are
preferred.

"$ 4bYfUbcbUQc_^cV_bdXYcbUcUQbSX
"$!3_^ce]Ub S_^fU^YU^SU* Y^SbUQcUT `UbV_b]Q^SU X_ecUX_\T
TUdUbWU^d
In any situation and for any product the consumer would like to have a
product that is convenient to use and has a good performance. A controlled or
sequential release detergent is likely to have an improved performance
compared to a traditional detergent. An additional advantage is that the
traditional powder formulation is preserved and thus the washing habits of the
consumer do not have to be changed.

"$"4USbUQcUgQcdU_VX_ecUX_\TTUdUbWU^dcU^fYb_^]U^d
Detergents are flushed away together with the washing water. The
washing water from a washing machine forms an important part of the
domestic wastewater. In the past several components of detergents have caused
environmental problems. Examples are the first synthetic detergents that used
non-biodegradable surfactants that caused excessive foam forming in water
purification plants and the use of sodiumtriphospate as builders which caused
excessive algal growth in surface water.
The use of a controlled release detergent would enhance the efficiency of
the used components and thus reduce the amount necessary in a detergent. Less
material means a lower concentration in the wastewater and thus a more
environmental friendly use of detergents.
Related to this environmental issue is the increasing pressure from the
European governments to reduce the impact of detergents on the environment.
The reduction of the environmental impact of detergents is described in the
European Commission's adoption of “a Recommendation for Good
Environmental Practice for Household Laundry Detergents” [http://www.
eubusiness.com/environ/980723co. htm].
The Recommendation is based on a voluntary measure, the
Environmental Code of Practice, proposed by A.I.S.E. (Association
Internationale de la Savonnerie, de la Détergence et des Produits d'Entretien)
representing more than 90% of the European detergents industry.
It sets the following targets: by the year 2002, compared with 1996, the
total amount of energy used per wash cycle should be reduced by 5%; the

'
9^db_TeSdY_^

consumption per capita of household laundry detergents and packaging of

these products should be reduced by 10%. The content of poorly biodegradable
organic ingredients for this product group should be decreased by 10% as well.

"$#3_]`UdYdYfU`_cYdY_^_``_bde^Ydi
The world detergent market (the word detergent only applies to those
products used for fabrics cleaning) was worth $25.62 billion in 1993. The
competition in the business is fierce with as biggest manufacturers on the
market Proctor & Gamble, Unilever, Henkel and Colgate.
This means that a lot of research is and has been done to improve the
washing characteristics or efficiency of the detergent. In the past this has led to
several revolutions in the detergent industry which were very profitable to
some manufacturers [1]. Examples are the addition of hydrogen peroxide to the
detergent (a mixture of perborate and silicate or Per-sil) in 1907. In the fifties the
first synthetic detergents emerged on the market that reduced the energy use of
the washing machines considerably, additionally a low-foaming detergent was
introduced (Dixan) that improved the washing performance of drum-type
washing machines. In the sixties the first enzymes were introduced into
detergents (Biotex). The enzymes improved the removal of protein stains. The
use of enzymes implied reduction of the temperature of the washing water,
which caused a reduced efficiency of the hydrogen peroxides. To solve this
problem Unilever introduced bleach activators in the seventies. A big change in
the eighties was the removal of phosphates from the formulation in favor of
zeolites.
A new dry powder detergent with controlled or sequential release would
be a new development giving improved washing characteristics and therefore a
competitive advantage.

"% @b_`UbdYUc_VdXU`b_TeSd

"%!3_^db_\\UTbU\UQcU`b_`UbdYUc*QTZecdQR\U\QWdY]U`e\cUbU\UQcU
There are some specific demands that the release profile of an active
component in a controlled release formulation for use in a detergent should
fulfill:
1. An (beforehand) adjustable lag-time (the time without any release of the
contents) up to 45 minutes,
2. a pulse release of the active component in the washing water after the lag-
time,

(
  3XQ`dUb"


3. the release should not be triggered by a change in environmental conditions

of the washing water such as a change in the temperature or pH.
The reason for the second demand is that the average washing process
takes approximately 45 minutes. Because of this rather short time the release of
any component after the lag-time has to be fast and complete to ensure that the
active component still has sufficient time to complete its task.
The reason for the third demand is that for dry powder detergents the
washing habits and products differ considerably around the world. Release
triggered by a change in temperature or pH would limit the use of the product
to a certain region. This does of course not mean that the release mechanisms of
the formulations developed in this thesis are independent of the pH or
temperature of the water in which they are dissolved. It means that the pulse
release of the active component may not be triggered by a change in the
properties of the water in which it is dissolved, i.e. the water in which the
formulations are dissolved is kept at the same temperature and pH during the
release experiments.
A simple hypothetical example of a sequential release washing process is
given in figure 2.1, the complete sequence of steps that may take place are still a
subject of investigation.

Figure 2.1 Hypothetical example sequential washing process.

)
9^db_TeSdY_^

"%"CdQR\UQdcd_bQWU
Controlled release formulations that have a positive influence on the
stability of the active components (i.e. form a protective barrier to any other
components) are preferred.

"%#@QbdYS\UcYjUTYcdbYRedY_^
The formulation should consist of particulate matter in the size range of
300 and 1000 µm. this ensures that the formulation can be incorporated into
existing powder detergents, without any segregation, dusting or flowability
problems.

"%$@XicYSQ\\icdb_^WV_b]e\QdY_^
Some active components in detergents (proteases, bleaches) can be a
potential health hazard to consumers or operators in the production plant. To
ensure there is no contact of the active with the consumer or operator the
formulation should be physically stable and should have sufficient mechanical
properties to prevent premature exposure of the active.

"%%5S_^_]YSQ\S_cd`bYSU
In this thesis no attempt is made to calculate the cost price of the
formulations. This means that it is possible that components are used that
would not be economically feasible in a real life detergent. On the other hand
we discarded formulations beforehand that would have needed an excessive
expensive component such as tailor made polymers.

"%&CSQ\QRY\YdicSQ\Ue`cSQ\UT_g^
All the production methods used in thesis are also used on a larger scale
in bulk production plants. No attempts were made to produce formulations that
would imply the use of a very complicated production method, which are
common in for example the pharmaceutical industry, such as coated tablets
with laser-drilled holes.
Also the production processes for the formulations described in this thesis
should be as environmental friendly as possible. This means that the use of
organic solvents in the production processes is not allowed. Therefore the
production of the products described in this thesis required no organic solvents.

! 
  3XQ`dUb"


"%'GQdUbY^c_\eR\UbU]QY^cY^gQcXY^WgQdUb
To prevent sedimentation of water-insoluble remains on the substrate (i.e.
clothes) the formulation should preferably consist entirely or for a large part of
water-soluble components.

"& CdbeSdebU_VdXU`b_TeSd

"&!<YdUbQdebU bUfYUg _^ dXU UhYcdY^W S_^db_\\UT bU\UQcUc

V_b]e\QdY_^c
Controlled release delivery systems and the concept of sustained or
prolonged release of an active agent has existed for decades. Especially in the
pharmaceutical area the applications for controlled release are numerous. Most
of the controlled release formulations developed are aimed at a constant release
rate of an active component over a certain period of time. This is done, for
example, to achieve a therapeutic level of a drug in the body over an extended
period of time without the need to administer the drug several times a day.
Another example is the controlled release of fertilizers for agricultural purposes
in which the fertilizer is slowly released to the environment over an extended
period of time.
The release profile investigated in this thesis, pulse release or immediate
release after a predetermined lag-time, is less well known. There are however
some examples in the pharmaceutical, agricultural and detergents area in which
pulse release can be beneficial.
For example, some hormones only exhibit their effect if they are
administered in pulses. A specific example is the effectiveness of the ovulation-
inducing hormone LHRH [2]. Pulsed delivery and continuous administration of
LHRH have opposite effects, the former leading to fertility and the latter to
infertility. Thus the effectiveness of LHRH in inducing ovulation in infertile
women depends on its administration in a precise on-off timed pattern.
An example in the agricultural area [3] is the distribution of pesticides on
farmland. In some cases it is desirable to release some insecticides or insect
pheromones in response to rain. This is done because many insect pests hatch
shortly after rain, when fields are too wet for farmers to enter with tractors to
spread pesticides. Thus a farmer could disperse pulse release devices when it is
dry which release their contents after rain when it is most effective.
In the following section some patents and articles on pulse release are
discussed. The emphasis is on inventions or formulations that consists of
particulate matter, i.e. spherical or nearly spherical particles in the size range of
0.1 to 2.0 mm.

!!
9^db_TeSdY_^

Pharmaceutical formulations with a pulse release; burst release

mechanism
In this part we describe formulations with a pulse release mechanism for
use in the pharmaceutical area. The release in these formulations is controlled
by the mechanical failure of a coating surrounding a core in which the active
ingredient is present. Furthermore we describe formulations with other release
mechanisms.
In 1967 Milosovich from the Parke, Davis & Company wrote a patent [4]
in which he describes a particulate controlled release dosage form containing
water-swellable beadlets. The background of the invention is that controlled
release from larger coated dosage forms (tablets) has some disadvantages. The
most important disadvantage being the risk of dose dumping due to failures in
the coating of the tablet. To solve this problem Milosovich coated gelatin cores
with a water-insoluble coating. When water diffuses through the coating into
the core the gelatin starts to swell, inducing coating failure and release of the
contents. Since that the active component is distributed over numerous cores
premature release of the individual microcapsules is not as serious as with a
single unit dosage form.
A similar device is described by Baker [5] in US patent 3952741. He states
that the formulation described in the patent from Milosovich is greatly
influenced by the pH of the release environment and other components present.
This is because the gelatin swelling depends on the factors just mentioned. To
work around this problem Baker incorporated water-soluble components in the
microcapsule. These components (sucrose or salts) do not swell but the
concentration gradient over the coating will induce a water flux through the
coating inducing an increase of the volume of the core. At a certain point the
coating will reach its maximum elongation and break thereby releasing its
contents. The time delay or lag-time between the time the device is placed in the
aqueous environment and the time it bursts can be controlled by:
• varying the thickness or area or composition of the semi permeable
membrane,
• varying the water-solubility of the component in the core thus increasing or
decreasing the osmotic pressure over the coating,
• varying the shape or size of the device.
Baker gives a wide range of possible shapes of the device ranging from
spherical to devices that rupture along a seam or a thin spot induced
beforehand.
Another patent on a controlled release device with a bursting coating,
assigned to Bausch & Lomb [6], is a proteolytic enzyme or a salt filled capsule. If
the enzyme is incorporated the enzyme will destroy the gelatin capsule wall by
hydrolysis of the polymer chains. If the salt is incorporated the release depends

!"
  3XQ`dUb"


on the amount of liquid diffused into the capsule. The application is that a
solution of hydrogen peroxide, in which contact lenses are disinfected, is
neutralized after a certain lag-time by a component present in the capsule. In
this way the contact lenses are given sufficient time to be disinfected by the
hydrogen peroxide without bringing the persons eye in contact with the strong
oxidizing agent.
Ueda et al have a patent [7] and published three articles [8-10] about a
particulate pulse release device which they named a Time controlled Explosion
System (TES). It consists of an inert core (polystyrene balls or non-pareil sucrose
beads) coated with respectively a drug layer, a swelling agent layer (low-
substituted hydroxypropylcellulose) and a water-insoluble layer
(ethylcellulose). When water diffuses through the ethylcellulose coating the
hydroxypropylcellulose layer will swell and rupture the ethylcellulose layer
inducing immediate release.
The lag-time is controlled by the thickness of the outer ethylcellulose
membrane. They found that the water permeation rate through the outer
coating is correlated with the reciprocal of the membrane thickness.
Hydroxypropylcellulose (HPC) was chosen as the swelling agent because
the swelling of this polymer is independent of the pH of the environment in
which it is immersed. Therefore the formulation has a release profile
independent of the pH. Another claimed advantage of this formulation is that
the release depends only on the swelling of the HPC layer and thus is
independent of the solubility of the drug in contrast to formulations depending
on release by diffusion of the drug through a rate limiting membrane. One
condition has to be met to achieve this swelling layer thickness dependent
release rate: the swelling layer has to be sufficiently thick to prevent premature
diffusion and dissolution of water into the drug layer.
The drug, HPC and ethylcellulose layers were applied in a fluid bed from
an organic solution.
Schultz and Kleinebudde [11] wrote an article on a device similar to the
bursting devices discussed before. In this case the formulation is somewhat
simpler, it consists of a water-soluble core coated with a water-insoluble film-
former (cellulose acetate). Release depends on the increase of the core volume
due to the diffusion of water though the coating. The coating is not totally
ruptured but pores are formed when a certain amount of water has diffused
into the core. Through these pores the active ingredient is released. Changing
the ratio between water-soluble and water-insoluble material in the core alters
the release profile from a release controlled by drug diffusion through the
coating to a pulse release profile.
In a follow up article [12] Schultz and Kleinebudde describe the relation
between the release properties and the mechanical properties of free cellulose
acetate films. They found that they could influence the release properties by

!#
9^db_TeSdY_^

using plasticizers in the cellulose acetate film with varying water solubility. The
water solubility of the plasticizer influenced the water permeability of the
coating and the dissolution rate of the plasticizer from the film. Also the amount
of plasticizers had a pronounced influence on the release properties.

Pharmaceutical formulations with a pulse release; other release

mechanisms.
A device dependent on the slow dissolution behaviour of high viscosity
polymers is described by Gazzaniga et al [13]. It consists of a core with therein
dispersed a drug substance which is coated with a high viscosity polymer
(hydroxypropylmethylcellulose 4000, abb. HPMC 4000) and an outer coating
which dissolves at a pH higher than 5. The outer film has the function of
protecting the system from the fluids in the stomach and dissolves when it has
entered the small intestine. The HPMC layer has as function to delay the release
of the drug for 3-4 hours when the system is transported through the small
intestine. The HPMC layer is capable of doing this because it dissolves and
erodes very slowly in water. The release profile obtained is a pulse release of the
drug after an initial lag-time.
The technical difficulty with this formulation is applying the HPMC
coating. This is done by a special technique [14], which involves dispersing the
HPMC in ethanol as discrete particles and adding water as a plasticizer to
enable film forming. A typical spraying formulation would consist of 83-w/w%
ethanol, 7-w/w% water, 5-w/w% HPMC and 3-w/w% talc as an anti-tack
additive and additional plasticizers such as polyvinylpyrrolidone, polyethylene-
glycol and diethylphtalate.
Narisawa et al [15, 16] developed a device capable of pulse release
depending on the change in diffusion properties of a copolymer of methacrylic
acid and ethyl acrylate (Eudragit RS) by uptake of acids. They found that a core
coated with Eudragit RS showed very slow release rates in pure water but
significant increase in the release rate was found when the microcapsules were
immersed in an organic acid solution. This was caused by structural changes in
the film caused by interactions of the acids with the quartenary ammonium
groups in the polymer. These interactions were used to achieve a pulse release
by incorporating an organic acid in the core of the formulation. They found that
the lag-time was shorter with increasing pKa of the incorporated acid and thus
weaker acids were more effectively interacting with the polymer.
In another article from Narisawa et al [16] the interaction between an
organic acid (succinic acid) and Eudragit RS is studied in more detail. They
found that both the dissociated and undissociated acid form enhance the water
permeability of the film, the dissociated form by electrostatic interaction and the
undissociated form by plasticizing the film.

!$
  3XQ`dUb"


In US patent 4933185 [17] from Wheatley et al a controlled release system

for delivery of a biologically active substance is described. The principle used to
achieve a pulse release is enzymatic degradation. The enzyme is selected to
degrade the core to a point at which the core can no longer maintain the
integrity of the skin, so that the capsule falls apart.
The capsule system consists of ionically cross-linked polysaccharide,
calcium alginate, which is ionically-coated with a poly-cationic skin of poly-L-
lysine. After immersion in water the enzyme degrades the calcium alginate until
its molecular weight has dropped to a point at which the polymer cannot
sustain the ionic interaction with the poly-L-lysine anymore and release is
initiated.
The system is produced by dropping a sodium alginate solution with
therein suspended the enzyme and the biologically active substance into a
calcium alginate solution. The sodium ions in the polysaccharide are replaced
for calcium ions, which initiates crosslinking in the polymer and solidifies the
droplets. Subsequently the cores are dropped into a dilute solution of poly-L-
lysine to form the ionically bound coating.

Pulse release in detergents

In this part pulse release formulations are described that were developed
specifically for the use in a dry powder detergent.

Improved enzyme stability and activity by delayed release

Enzymes can catalyze specific biochemical reactions such as the
conversion of starch to amylo dextrins and sugar (amylase), the hydrolysis of
fats to glycerol and fatty acids (lipase) and the hydrolytic breakdown of proteins
(protease). The breakdown of these biological materials into smaller molecules
increases the solubility and thus enhances the cleaning of the substrate (e.g.
clothes).
Olson [18] describes in US patent 5733763 a composition capable of
releasing enzymes in an aqueous environment without being deactivated by
bleaches. The cleaning actions of enzymes and halogen bleaches are
complementary; each attacking different kind of soils. However halogen
bleaches tend to instantly deactivate enzymes at a concentration as low as 1 part
active halogen per one million parts cleaning media. Olson found that the
enzymes could be used more efficiently by encapsulating the enzyme in a
delayed release coating and using a bleach-neutralizing compound.
The main idea behind this formulation is that the halogen bleaches
dissolve fast into the washing water and oxidize the large colored molecules.
After a certain amount of time the bleach-neutralizing compound is released

!%
9^db_TeSdY_^

into the water removing any remaining active bleach in the medium. Finally the
enzyme is released which is than protected from deactivation by bleach.
To achieve this release profile Olson used several formulations. One
formulation is a core consisting of enzyme and filler coated with a bleach
neutralizing compound and a delayed release coating. Another formulation
described consists of two types of cores, enzyme and bleach-neutralizing cores,
each coated with different amounts or types of delayed release coating in such a
way that the bleach-neutralizing compound is released before the enzyme. As
bleach-neutralizing compound Olson used sodium-perboratemonohydrate or
sodium sulphate. As delayed release coatings were used sodiumcarboxymethyl-
cellulose and hydroxypropylcellulose.
No data is given for the release properties of the formulations but the
inventor aims at a delayed release of 2-6 minutes for the bleach neutralizing
compound and 0.5-2 minutes later the enzyme release.
Economics laboratory Inc. have a patent [19] on a formulation that should
improve the cleaning performance of enzymes by reversing the strategy of
Olson i.e. delaying the release of the oxidant bleach. This is achieved by coating
bleach particles. However, they state that the encapsulation of the bleaches to
protect the enzymes alone is not sufficient. This is due the instantaneous release
of bleaches caused by damaged or imperfectly coated capsules. Therefore
reducing agents are incorporated to deactivate small amounts of bleach from
damaged capsules to prevent premature deactivation of enzymes by these
bleaches. An example is a potassium dichloro-isocyanurate bleach encapsulated
in ethylene vinyl acetate which was added to 2 liters of water. In the water was
dissolved an enzyme, a detergent and a reducing agent. It was seen that the
release of the bleach in the water was delayed for 5 minutes after which the
enzyme activity rapidly decreased to zero.
Proctor & Gamble [20-24] has patents that describe formulations with a
similar goal as the patent from Olson; controlled release of an enzyme
compared to another compound. The release of the enzyme can be delayed
compared to another compound, or, the release of another compound is delayed
compared to the enzyme. Furthermore Proctor & Gamble do not restrict the
patents to just enzymes, also the delayed release of other compounds is
described such as a peroxyacid bleach compared to a surfactant.
For example in WO patent 97/235593 [21] the delayed release of a calcium
chelating agent is described. The calcium chelating agent acts as a water
softener and increases the stain removal. When the chelating agent is released
immediately in the washing water from the beginning of the washing process
the calcium in the water is immediately removed. Proctor & Gamble claim that
this can cause problems for the enzyme activity because some enzymes are only
active when a certain amount of calcium ions are present in the water. To solve
this problem the dissolution of the chelating agent is delayed. Delayed release is

!&
  3XQ`dUb"


achieved by coating granules with hydrophobic substances or agglomeration to

increase the size and density of the particles.
Another example is the delayed release of peroxy acid bleaches relative to
a surfactant [22]. Proctor & Gamble claim that the color stability of fabrics is
enhanced when the rate of release of bleach is slow and the absolute
concentration of the bleach in the washing water is low. They aim at a t50% (that
point in time at which 50 % of the component is released) of the surfactants
within 60 seconds and a t50% of 240 seconds for the delayed release of the
bleaches.
Similar claims (with variations in the components for the fast and the
delayed release) are made in the other patents, however not many details about
the production process or release profiles are given.
Genencor [25] has made an enzyme-containing granule coated with
hydrolyzed polyvinylacetate (PVA) or a copolymer thereof. It consist of a
soluble core (e.g. sugar, salt, starch) which is coated with four layers. These
layers are respectively a PVA layer, a layer of PVA mixed with the enzyme, a
chlorine scavenger layer (e.g. ammonium sulphate or ammonium citrate) and a
outer coating of vinyl polymer. They also mention the delayed release
characteristics of this product which protects the enzymes from oxidation or
autocatalytic degradation until sufficient amount of stabilizing proteins and
peptides are released from the dirty clothes in the washing water. A very
similar but more recent patent [26] describes essentially the same formulation.
Gist Brocades [27] has a patent on a device which incorporates liquid
enzyme in a granule with a porous structure, and is coated with a film forming
polymer. The cores consist of soda or sodiumchloride, the liquid enzyme
solutions are on a polyethyleneglycol (PEG) or glycerol basis and the coating is
a soluble cellulose derivative or acrylic polymer (Eudragit).
Novo [28] describes a device that comprises a core of an enzyme
containing material (enzyme and sodium sulphate) with a coating, which is a
mono- and/or diglyceride of a fatty acid (palmitic or stearic acid). They claim
that only this coating out of many tested will improve the enzymatic stability
without any unwanted side effects. They also use a sub-coating (beneath the
fatty acid coating) consisting of or containing an antioxidant (e.g. a
thiosulphate) which improves the stability of the enzymes in presence of
powerful bleaching agents. The production can be done in different manners,
e.g. by introducing the cores above the melting temperature of the coating in a
rotating mixer after which the coating is added and the product is removed
after cooling, or with a centrifugal extrusion device. The core is produced by a
high intensity granulating proces [29] and typically consists out of 25 % Alcalase
powder, 50% NaCl or Na2SO4, 10% cellulose fibres, 10% binder (yellow dextrin)
and 2% TiO2, all percentages based on weight. The use of a high intensity
granulation was a new development in detergent enzyme granulation, until

!'
9^db_TeSdY_^

now the granulation process could not be sufficient controlled. The reasons
were that during enzyme granulation a thick and not easily removable layer of
the solid material builds up on the granulator wall. Furthermore the mixture of
salt and enzyme powder is difficult to granulate in the high-shear mixer since
the transition from sufficiently wetted to an over wetted mixture requires a very
small amount of water. Novo solved this problem by including the cellulose
fibres, they are believed to be responsible for preventing buildup on the walls
and for affording a greater control of particle growth.
In another patent of Novo [30] a device for two kinds of enzymes is
described. It consists of a core of a primary enzyme, cellulose fibers and sodium
sulphate, coated with a sustained release layer which itself is surrounded by a
shell comprising of the secondary enzyme mixed with binder, filler, and
granulating agents. Finally this shell is coated with a non-dusting layer (PEG
4000). For example, the primary enzyme is a protease and the secondary a
lipase, so the lipase is released fast in the washing water and the protease
slowly which improves the stability of the lipases in the washing water. The
sustained release layer can be a mono-, di-, trigyceride of a fatty acid (Grindtek
MSP90).
A very similar formulation is described in a more recent patent (US
5733763) [31] with the difference that the production of the formulation is now
completely carried out in a drum-granulator. This is done by sequential
addition of the components to the granulator. Novo claims that this method is
easier to scale-up compared to for example fluid bed coating methods.
A delayed release formulation of Novo for peroxidase enzymes is
described in WO patent 95/33039 [32]. The formulation is developed for dye-
transfer inhibition, i.e. inhibition of fabric-to-fabric transfer of dye during
washing. Dye-transfer inhibition is achieved by bleaching of the washing water
(i.e. removal of coloration by degradation of dye dissolved in the washing
liquor) by enzymatic means. The enzymes used for dye-transfer inhibition are
peroxidases together with an accelerator. The peroxidase enzymes should be
released in the washing water when the other oxidation-sensitive components,
such as other enzymes, have been able to perform their intended function. This
is achieved by applying 10 to 40-w/w% water-insoluble coating on a core with a
comparable composition as in the patent described above [30].
Another reservoir device (a device consisting of a core with therein the
active ingredient surrounded by a release rate limiting coating) in relation to
detergents is made by EKA Nobel [33] it consists of a core of a bleaching agent
with a filler coated with a hydrophobic substance with therein dissolved
surfactants and containing water swellable grains. The water swellable grains
will absorb water and expand in volume. This expansion will break the
hydrophobic coating and thereby inducing fast dissolution of the bleaching
agent. The surfactants dissolved in the hydrophobic coating increase the rate of

!(
  3XQ`dUb"


water absorption. The core consists out of a peroxy bleaching agent and a filler
such as sodium sulphate. The hydrophobic coating is a natural occuring
polymer, such as an animal or vegetable fat, because they are cheap and
environmental friendly. To improve the mechanical strength and moisture-
barrier properties of the coating, synthetic polymers like polyethylene or ethyl
cellulose are incorporated. Preferred swellable grain materials are cold water
soluble starch and starch derivatives. The microcapsules are prepared by
making a suspension of the cores and the swellable grains in the molten coating
material with therein dissolved a surfactant. The suspension is fed to a rotating
disc and active or passive cooling solidifies the formed droplets. Fluid bed
coating of the cores is also possible.

Improved bleach performance by controlling the pH of the washing

water
Chemical bleaching is employed to remove organic colors from fabrics
and is carried out with oxidizing agents. The color of the stains is often derived
from a complicated organic molecule having a variety of reactive or unsaturated
groups and bonds. The oxidizing agent attacks these molecules and oxidizes
them to less complicated molecules which are commonly colorless.
The most widely used compound in laundry detergents is sodium
perborate and more recent because of concerns on the impact of boron salts on
the environment sodium percarbonate. Since the activity of these oxidizing
agents is very low below 60 ºC compounds described as bleach activators have
been added to the detergents that activate the oxidizing agents at lower
temperatures.
The formation of the activated oxidizing agents is optimal in an aqueous
solution at a relatively high pH level of about pH 9.5-11. However the resulting
bleaching agents provide optimum bleaching performance at a pH below 9.
Three patents are discussed below where a similar solution to this problem is
described i.e. the delayed release of an acid in highly alkaline washing water.
The first patent (EP0290081) [34] describes an improvement in the
washing performance when a sulfuric acid solution is added to the washing
water after an initial high pH period of 5-6 minutes. This brings the pH down to
a lower level at which the washing cycle is completed. As a practical solution
for the addition of acid it is suggested to use a sachet containing an acidic
substance or encapsulated or coated acid particles. No further details about how
this formulation should be produced, or which compounds should be used, are
given.
The author of the second patent (EP0396287) [35] has approximately the
same ideas on how long the initial high pH period should last and the
difference in the pH before and after the addition of the acid. The pH of the

!)
9^db_TeSdY_^

initial stage should be 10-11 for about 5 minutes and the completion of the
washing cycle should be at a pH level of 8-9.
The inventor gives several suggestions how delayed release of the acid
should take place. Most ideally the acid should be pumped into the washing
machine with an external pump at a certain point in time. In this way a pulse
release of the acid is obtained and the decrease in pH can be controlled most
ideally.
A more practical solution is the coating of citric acid particles with 10-
w/w % paraffin wax. The paraffin wax provides in a delay in the release in that
it must first be melted or dissolved by the washing water before the acid is
effectively released into the washing solution. The effective pH curve obtained
by this formulation is a first-order decrease of the pH, without an initial period
with a constant high pH, until the final pH is reached.
Another option is generating acid by chemical hydrolysis of a methylester
of an acid. The release rate can be adjusted by changing the substituent R on the
acid with the general formula ROCH3. Comparison of different types of esters
listed illustrates that methyl glycolate hydrolyzes relatively slowly. Faster
reactivity, and thus faster acid release, is observed with the other esters having
substituted reactive groups of -Cl, -Cl2 and -NO2. The release profile obtained is
first order in kinetics.
The final example given is the control of the acid release rate by changing
the chain length in aliphatic dicarboxylic acids. The higher the number of
carbon atoms in the chain the longer the dissolution time and thus the slower
the acid release rate. In this way a release profile is obtained similar to the
previous example.
The third and most recent patent (US5716923) [36] describes the coating of
sodium percarbonate bleach with alkali metal carbonate and an alkali metal
sulfate salt. The coating is applied because the sodium percarbonate is relatively
unstable in a detergent environment especially in moist or warm atmospheres.
The coating gives a retention of the solution of the bleach in the washing water
and this normally means a decrease in washing performance. However when a
controlled pH release method is used the cleaning performance can be
enhanced. To achieve this controlled pH release method the author suggests the
use of coated acid particles. The recommended acid to use is citric acid because
it has the advantage of providing builder capacity to the wash solution. As a
coating a dual coating is preferred with an inner coating of wax (paraffin with a
melting point in the range 50 ºC to 90ºC) and an outer silica coating. This dual
coating allows for improved particle flow and control over the dissolution rate.
As a production method the author suggests agglomeration or spraying the
solutions on a moving bed of particles.

" 
  3XQ`dUb"


Reduced fabric deposition of sediments by controlled release of

detergent components
A formulation that uses a pH controlled washing process to prevent
sedimentation of crystals on fabrics is described in US patent 4210550 [37] from
Akzo NV. The detergent formulation makes use of alkali carbonates to remove
multivalent ions from the washing water. This has as a disadvantage that
carbonate precipitates will be formed on fabrics. However the impact of the
precipitates that originate from one washing cycle is hardly noticeable, thus if
the precipitates are removed from the fabrics in each washing cycle alkaline
carbonates can be used as builders. This can be achieved by exposing the fabrics
to an acidic environment which will dissolve the precipitates on the fabrics.
The author suggests a pH controlled washing process in which the acid
dissolves fast in the washing water (and other components that are more active
at a low pH), and the alkali carbonates exhibit a delayed dissolution. An
example given is alkali carbonate particles prepared by extruding and
marumerizing and subsequently coated with a mixture of copolymers of
methacrylic acid and ethylacrylate (Eudragit L30D and Eudragit E30D). This
formulation will dissolve in water after 3 to 6 minutes and thus an acidic
environment is sustained for 3-6 minutes after which the pH will increase.
A patent from Church & Dwight [38] describes a formulation with
essentially the same background as the patent described above. They also claim
to prevent sedimentation on the fabrics caused by alkali carbonates by a
delayed release washing process. They use polymeric polycarboxylates to
remove multivalent ions from the washing water. These polymers are very
effective sequestering and dispersing agents as well as crystal growth inhibitors.
However polycarboxylates are not biodegradable and thus not environmental
friendly. Church & Dwight found that the polycarboxylates were used more
efficiently when they were used in slow-dissolving granules rather than in the
form of a fast dissolving powder. Thus delaying the release of the
polycarboxylates can decrease the amount needed in the detergent and decrease
the impact on the environment.
The aim for the delayed release period was 130-160 seconds after the
soluble carbonate was dissolved. This was achieved by increasing the particle
size of the polymer particles and incorporating a diluent salt and a binder.
The most recent patent on the prevention of sedimentation on fabrics by a
multi-stage washing process is described by Henkel KGaA [39]. The
formulation consists of granulated washing components with a part having
delayed release properties and a part that dissolves fast. The main fast
dissolving component is citric acid that will remove depositions from the fabrics
and the washing machine. Most of the other components are released after this
initial acidic time period. Henkel aims at an acidic time period of 5 minutes, 3
minutes after the washing process has started.

"!
9^db_TeSdY_^

Delayed release of antifoam additive

In EP 0336710 [40] from Dow Corning inc. a formulation is described for
the delayed release of an anti-foam additive. Less foam is beneficial to the
washing process because surfactant present in the foam does not aid anymore in
rinsing the fabric. However, the anti-foam should not be released immediately
because this will prevent the formation of any foam and a person doing the
wash might wrongly conclude that not enough detergent is added to the water
or that the detergent lacks efficacy. Therefore Dow Corning developed a
delayed release formulation for the antifoam consisting of high-viscosity water-
soluble cellulosic polymers agglomerated with the antifoam. This resulted in a
formulation which, when added to water containing surfactant, did not
suppress the foam formation for 6 minutes. After this period the speed of foam
production is decreased until the foam formation is completely stopped after
approximately 10 minutes.

"&"3_^S\ecY_^\YdUbQdebU*bUcUbf_YbTUfYSU]_cdceYdQR\U

The conclusion we can draw from the available literature is that a device
which consists of a core with therein the active surrounded by a protecting and
release rate controlling coating is the most used in pulse release devices.
Advantages are the strict separation between the release rate controlling
part and the part containing the active which are essential conditions if a pulse
release profile is desirable, and the protective function of the coating which acts
as a barrier to other harmful components.

"' 3_^S\ecY_^c

The most important goal of the product developed in this thesis is the
enhanced performance of a dry powder detergent by sequential release of the
active ingredient in the washing water. To achieve this goal the product
developed in this thesis should fulfill certain demands the most important
being:
1. an (beforehand) adjustable lag-time (the time without any release of the
contents) up to 45 minutes,
2. a pulse or immediate release of the active components in the product in the
washing water after the lag-time,
3. it should consist out of particulate matter in the size range 0.3-1.0 mm,

""
  3XQ`dUb"


4. it should have sufficient mechanical properties to prevent premature

exposure of the active during handling, storage or use,
5. it should have a positive influence on the stability of the active ingredient
during storage.
From the literature it was found that formulations most likely to fulfill
these demands are reservoir devices: a core with the active ingredient
surrounded by a release rate controlling coating. From this conclusion and the
results of our own preliminary experiments we put the emphasis in this thesis
on reservoir devices with different types of coating, in which the coating
determines the release mechanism.

"#
9^db_TeSdY_^

"( BUVUbU^SUc

1. Rispens, S.I., Revoluties in wasmiddelen, in Trouw. 1996: Amsterdam. p. 15.

2. Theeuwes, F., Triggered, pulsed and programmed drug delivery., in Novel drug delivery and
its therapeutic application, L.F. Prescott and W.S. Nimmo, Editors. 1989, John Wiley &
Sons Ltd: Chihester. p. 323-340.
3. Kuethe, D.O., et al., Design of capsules that burst at predetermined times by dialysis. Journal
of Controlled Release, 1992. 18: p. 159-164.
4. Milosovich, G. and A. Arbor, Controlled release dosage form containing water-swellable
beadlets. patent # : 3,247,066; Parke,Davis & Company; 1966; US; p. 1-8.
5. Baker, R.W., Controlled release delivery system by an osmotic bursting mechanism. patent # :
US3,952,741; Bend Research Inc.; 1976; US, Oregon; p. 1-9.
6. De, N.C. and A.M. Salpekar, Controlled release composition for active substances into an
aqueous medium. patent # : US5645848; Bausch & Lomb Inc.; 1997; US; p. 1-5.
7. Ueda, Y., et al., Time controlled explosion systems and process for preparing the same. patent
# : US4871549; Fujisawa Pharmaceutical company Ltd; 1989; Japan; p. 1-4.
8. Ueda, S., et al., Development of a novel drug release system, time controlled explosion system
(TES). I. Concept and design. Journal of Drug Targeting, 1994. 2(1): p. 35-44.
9. Ueda, S., et al., Development of a novel drug release system, time controlled explosion system
(TES). II. Design of multiparticulate TES and in vitro drug release properties. Chemical and
pharmaceutical bulletin / Pharmaceutical Society of Japan, 1994. 42(2): p. 359-363.
10. Ueda, S., et al., Development of a novel drug release system, time controlled explosion system
(TES). III. Relation between lag time and membrane thickness. Chemical and pharmaceutical
bulletin / Pharmaceutical Society of Japan, 1994. 42(2): p. 364-367.
11. Schultz, P. and P. Kleinebudde, A new multiparticulate delayed release system. Part I:
Dissolution properties and release mechanism. Journal of Controlled Release, 1997. 47: p.
181-189.
12. Schultz, P., I. Tho, and P. Kleinebudde, A new particulate delayed release system. Part II:
Coating formulation and properties of free films. Journal of Controlled Release, 1997. 47: p.
191-199.
13. Gazzaniga, A., et al., Oral delayed-release system for colonic specific delivery. International
journal of Pharmaceutics, 1994. 108: p. 77-83.
14. Maffione, G., et al., High-viscosity HPMC as a film-coating agent. Drug development and
industrial pharmacy, 1993. 19(16): p. 2043-2053.
15. Narisawa, S., et al., An organic acid induced sigmoidal release system for oral controlled release
preparations. Pharmaceutical Research, 1993. 11(1): p. 111-116.
16. Narisawa, S., et al., An organic acid induced sigmoidal release system for oral controlled release
preparations. 2. Permeability enhancement of Eudragit RS coating led by the physicochemical
interactions with organic acid. Journal of Pharmaceutical Sciences, 1996. 85(2): p. 184-188.
17. Wheatley, M.A., R.S. Langer, and H.N. Eisen, System for controlled release of biologically
active compounds. patent # : US4933185; Masschusetts Institute of Technology; 1990; US;
p. 1-3.
18. Olson, K.E., Water insoluble encapsulated enzymes protected against deactivation by halogen
bleaches. patent # : US4965012; ; 1990; US; p. 7.
19. Anderson, C.R. and T.R. Oakes, Compatible enzyme and oxidant bleaces containing cleaning
composition. patent # : US4421664; Economics Laboratory Inc.; 1983; US; p. 1-8.
20. Jeffrey, J., J.S. Park, and B. Stoddart, Detergents containing a builder and a delayed release
enzyme. patent # : WO95/28469; Proctor & Gamble company.; 1995; GB; p. 1-18.

"$
  3XQ`dUb"


21. Cullen, K., Detergent composition comprising enzyme and delayed release mechanism. patent
# : WO 97/23593; The Proctor & Gamble Company; 1997; ; p. 1-27.
22. Jeffrey, J., J.S. Park, and G.M. Baillely, Detergents containing a surfactant and a delayed
release peroxyacid bleach system. patent # : US5755992; The Proctor & Gamble company;
1998; ; p. 1-26.
23. Baston, G.M., J. Jeffrey, and G.M. Baillely, Detergents containing an enzyme and a delayed
release peroxyacid bleaching system. patent # : WO 95/28467; The Proctor & Gamble
Company; 1995; GB; p. 1-17.
24. Baillely, G.M., J. Jeffrey, and J.S. Park, Detergents containing a surfactant and a delayed
release enzyme. patent # : WO95/28466; The Proctor & Gamble company; 1995; ; p. 1-15.
25. Arnold, R.E., et al., Enzyme containing granules coated with hydrolyzed polyvinyl alcohol or
copolymer thereof. patent # : 5324649; Genencor International Inc.; 1994; US patent; p. 1-
12.
26. Dale, A.D., et al., Coated enzyme-containing granule. patent # : US5879920; Genencor
International Inc.; 1999; US; p. 1-7.
27. Andela, C., et al., Process for dust-free enzyme manufacture. patent # : WO 94/26883; Gist
Brocades N.V.; 1994; NL; p. 1-13.
28. Markussen, E.K. and P. Falholt, Granulate detergent enzyme product, method for production
thereof, use thereof, and detergent containing such product. patent # : WO 89/08694; Novo
industri A/S; 1989; DK; p. 1-22.
29. Kadam, K.L., Granulation processes for industrial enzymes., in Granulation technology for
bioproducts., K.L. Kadam, Editor. 1990, CRC press: Boca Raton, Florida. p. 297-313.
30. Markussen, E.K. and P. Falholt, Enzyme containing granulate and method for production
thereof. patent # : WO 90/09440; Novo Nordisk A/S; 1990; DK; p. 1-25.
31. Markussen, E.K. and P. Falholt, Enzyme granulate formed of an enzyme-containing core and
an enzyme-containing shell. patent # : US5733763; Novo Nordisk A/S; 1998; Denmark; p.
1-15.
32. Damhus, T. and D.A. Petersen, Dye-transfer inhibitory preparation and detergent
composition comprising such a preparation. patent # : WO95/33039; Novo Nordisk; 1995;
Denmark; p. 1-6.
33. Langemo, L., R.E. Sparks, and I.C. Jacobs, Bleaching agent. patent # : EP 0 573 731 A1;
EKA Nobel industries AB; 1992; Sweden; p. 1-9.
34. Barnes, S.G., Improved detergent bleach composition and method of cleaning fabrics. patent # :
EP0290081; Unilever NV; 1988; ; p. 1-6.
35. Kong, S.B., S.D. Ratcliff, and D.S. Steichen, Method and product for enhancing bleaching
with in situ peracid formation. patent # : EP0396287; The Clorox Company; 1990; US; p. 1-
9.
36. MacBeath, F.S., Laundry detergent containing a coated percarbonate and an acidification agent
to provide delayed lowered pH. patent # : US5716923; The Proctor & Gamble Company;
1998; US; p. 1-11.
37. Cornelissens, E.G., Detergent composition containing an alkali carbonate. patent # :
US4210550; Akzo NV; 1980; Netherlands; p. 1-5.
38. Falotico, A.J., S.A. Bolkan, and L.R. Mazzola, Carbonate built laundry detergent
composition containing a delayed release polymer. patent # : US 5496376; Church & Dwight
Co., Inc,.; 1996; ; p. 1-11.
39. Rahse, W., et al., Feste Wertstoffbereitungen fur die mehrstufige Textilwasche. patent # :
DE4438850 A1; Henkel KGaA; 1996; Deutschland; p. 1-18.
40. Starch, M.S., Delayed release antifoam additives patent # : EP890303315; Dow corning (US);
1989; US; p. 1-5.

"%
9^db_TeSdY_^

"&