FIELD OF THE INVENTION
The present invention is directed to compositions and processes for medicinal capsule shells,
in particular the present invention relates to an aqueous composition for the manufacture of
hydroxypropyl methyl cellulose hard capsules (HPMC) and a method of preparing the
hydroxypropyl methyl cellulose hard capsules obtained therewith.
BACKGROUND OF THE INVENTION
Capsules are well-known dosage forms that normally consist of a shell filled with one or
more specific substances. The shell may be a soft or, as in this invention, a hard stable shell
comprising film-forming polymer(s) such as gelatine, modified starches, modified celluloses
etc. Hard capsules are generally manufactured by using a dip moulding process. In this
process, pin moulds are dipped into a film forming composition. By gelling the film forming
polymer on the pin, a film is formed that is subsequently dried on the pin, to obtain a capsule
shells. The shells are then stripped of the pins and cut to a desired length. Thus, capsules caps
and bodies are obtained that can later be joined such that an empty pre-locked capsule is
obtained.
When using this type of dip moulding process, it is necessary to ensure that the dipping
composition adheres to the pin surface and quickly gels, once the pins are withdrawn from
the dipping bath. This avoids that the composition flows on the pins surface so as to achieve
the desired shell or film distribution to manufacture capsules. When using gelatine as the film
forming polymer, the dipping compositions, gel with cooling. The same gelling behaviour is
2
shown by mixtures of methyl cell uloses .and gelling agents. Both these types of film forming
polymers may be processed on conventional devices for manufacturing hard capsules.
US 2526683 discloses a process for preparing methyl cellulose medicinal capsules by a dip
coating process. The process consists of dipping a capsule forming pin pre-heated to 40° C.-
85" C. into a methyl cellulose composition maintained at a temperature below the temperature
where gelation begins, withdrawing the pins and placing the pins in ovens at temperatures
above the gelation temperature and drying the film. When the hot pins are dipped into the
composition, the composition gels on the surface of the pin and as the pin is withdrawn, a
film of gelled liquid of a certain thickness is formed on the pin. The pin is then generally
turned 180" to an upright position and typically placed in the oven to dry. This technique is
conventionally named "thermogelation". The dry capsule is then stripped, cut to size and the
body and caps are fitted together. However, methyl cellulose is insoluble in water under 37"
C.
US 3,493,407 discloses the use of non thermal gelling dip-molding compositions of some
hydroxyl alkyhnethyl cellulose ethers in aqueous solvents. The pins must be kept in rotation
for more than half an hour to obtain capsules with a regular shape.
US. 3,617,588 discloses the use of an induction heater to gel cellulose ether.
US 4,001,211 discloses improved thermogeling compositions based on a blend of methyl
cellulose and hydroxypropyl methyl cellulose.
The compositions and processes described above did not make it possible to obtain highperformance
manufacturing of hard capsules both with regard to speed, dissolution properties
and with regard to overall quality. Similarly, capsules manufactured by combination of
3
HPMC with gelling agents have very poor visual quality and dissolution properties since they
are sensitive to pH.
In the conventional methods the starting material used was HPMC 2906 grade. Said methods
or processes did not involve gelling and co gelling agents and also do not make a mention of
the concept of dipping of pins.
Despite the aforementioned prior arts and disadvantages, the present inventors have made a
great effort to solve the technical problems of conventional arts, and develop an aqueous
composition for the manufacture of hydroxypropyl methyl cellulose hard capsules (HPMC)
of high quality and e.g. standardized dimension, high transparency and excellent dissolution
and mechanical performance and a method of preparing said hydroxypropyl methyl cellulose
hard capsules.
OBJECTIVE OF THE INVENTION
The main objective of the present invention is to overcome the limitations of the prior art.
An objective of the present invention is to provide aqueous composition for the manufacture
of hydroxypropyl methyl cellulose hard capsules (HPMC) of high quality, transparency and
excellent dissolution.
An objective of the present invention is to provide aqueous composition for the manufacture
of hydroxypropyl methyl cellulose hard capsules (HPMC), wherein the composition majorly
comprises of hydroxypropyl methyl cellulose, methoxy and hydroxypropoxy in a suitable
range(%).
Another objective of the present invention is to provide HPMC hard capsule shells obtainable
fi·om the aqueous compositions of the invention show good clarity and transparency.
4
Another objective of the present invention is to provide an aqueous composition for the
manufacture ofhydroxypropyl methyl cellulose hard capsule shells, wherein at least one inert
non-toxic pharmaceutical grade or food grade pigment is incorporated in the aqueous
compositions for obtaining coloured capsules.
Another objective of the present invention is to provide an aqueous composition for the
manufacture of hydroxypropyl methyl cellulose hard capsules, wherein the compositions can
be used as dipping compositions in dip-moulding processes for the manufacture of HPMC
hard capsules.
Another objective of the present invention is to provide a process for preparing HPMC hard
capsules according to a dip coating process.
Yet another objective of the present invention is to provide hydroxypropyl methyl cellulose
hard capsule shells for the manufacture of pharmaceutical dosage forms suitable for the
administration to a subject of pharmaceutical substances in solid form.
Yet another objective of the present invention is to provide hydroxypropyl methyl cellulose
hard capsule shells whose bodies and caps telescopically joined can suitably be sealed and is
a cost-effective solution for the manufacture of liquid-filled oral dosage forms as well as
powder-filled dosage forms for inhalation or the manufacture of tamper-proof pharmaceutical
forms to be used in the context of double-blind trials.
These and other objectives of the present invention will be apparent from the
drawings/photographs and descriptions herein. Every object of the invention is attained by at
least one embodiment of the invention. However, no embodiment necessarily meets every
object set forth herein.
5
SUMMARY OF THE INVENTION
The present invention envisions an aqueous composition for the manufacture of
hydroxypropyl methyl cellulose hard capsules (HPMC) shells and a method of preparing said
hydroxypropyl methyl cellulose hard capsules obtained therewith.
According to a preferred embodiment of the present invention, the composition comprises of
18% - 23% by weight of hydroxypropyl methyl cellulose with methoxy content of 27.0% -
30.0% (w/w); hydroxypropoxy content of 7.0%-12% (w/w) along with a viscosity grade
ranging between 3.5 cPs -6.0 cPs as a 2%weight solution in water at 20° C.
According to another embodiment of the present invention, the aqueous composition further
comprises of non animal-derived film-forming polymers (0-5%); gelling system (cations and
anions) (1.5-2.5%); at least one ine11 non-toxic pharmaceutical grade or food grade pigment
(0.001 - 1 .0%) and a plasticizer (0- 2%) by weight over the total weight of the composition.
According to another embodiment of the present invention, the viscosity of the HPMC 2%
weight solution in water at 20'C is measured according to the USP30-NF25 method for
cellulose derivatives.
According to another embodiment of the present invention, non animal-derived film-forming
polymers are selected from group comprising polyvinyl alcohol, plant-derived or bacterialderived
film-forming polymers; plant-derived film- forming polymers may be starch, starch
derivatives, cellulose, celluloses derivatives; bacterial-derived film-forming polymer may be
exo-polysaccharides selected from xanthan, acetan, gellan, welan, rhamsan, furcelleran,
succinoglycan, scleroglycan, schizophyllan, tamarind gum, curdlan, pullulan, dextran and
mixtures thereof.
6
According to another embodiment of the present invention, the gelling system comprises of
cations selected from the list comprising K", Na+, Li+, NH4+, Ca++, Mg++ and mixtures
thereof and/or one or more gelling agents selected from the list comprising guar gum, locust
bean gum(carob), carrageenans, tara gum, gum arabic, ghatti gum, khaya grandifolia gum,
tragacanth gum, karaya gum, pectin, arabian (araban), xanthan, gellan gum, konj ac mannan,
galactomannan, funoran, and mixtures thereof.
According to another embodiment of the present invention, the inert non-toxic
pharmaceutical grade or food grade pigment (0.001 - 1.0 %) is preferably titanium dioxide
and the plasticizer (0- 2%) is preferably glycerin or propylene glycol included in the aqueous
composition by the total weight of said composition.
According to another preferred embodiment of the present invention the method of
preparation of hydroxypropyl methyl cellulose capsule shells according to a dip coating
process, comprises the steps of:
a. preparing a aqueous composition of a hydroxypropyl methyl cellulose having
methoxy of content 27.0% - 30.0% (w/w); hydroxypropoxy of content 7.0%-12%
(w/w) and with a viscosity grade ranging between 3.8 cPs -5.6 cPs as a 2% weight
solution in water at 20°C; wherein concentration of said hydroxypropyl methyl
cellulose generates a viscosity of said composition of 1200 to 3000 cPs measured at a
temperature of 20° C.
b. maintaining plurality of pins of a predefined size at temperature ranging between
23'C- 24°C;
c. dipping said plurality of pins into said aqueous composition to obtain a dipped
composition;
d. maintaining said composition obtained in step (c) at a temperature ranging between
44°C-46°C below its gelling temperature;
e. withdrawing said dipped plurality of pins from said aqueous composition, thereby
obtaining a film on said dipped plurality of pins; and
f. drying said film of step (e) in an oven for a period of time, typically from 75 to 90
minutes on said dipped pins at a temperature ranging 33°C-35T to obtain a moulded
capsule shell (bodies and caps) on said plurality of pins;
g. lubricating said plurality of pins by using a de-moulding agent; and
a. dismantling said capsule shells (bodies and caps) from said lubricated plurality of pins
to a predetermined length;
b. joining said bodies and caps to obtain a pre-locked capsule;
In another embodiment of the present invention the capsule cap and body are telescopically
joined together so as to make their side walls partially overlap and obtain a capsule.
In a preferred embodiment of the present invention, the capsule shell prepared comprises of
88% - 92% of HPMC (methoxy content of 27.0-30.0% (w/w), a hydroxypropoxy content of
7.0-12% (w/w) and a viscosity of3.8-5.6 cPs as a 2% weight solution in water at 2WC; 1%-
3% non animal derived film-forming polymers, 1% to 8% water; at least one plasticizer
between 0-5%; at least one antibacterial agent between 0- 0.5%; at least one flavouring agent
between 0- I%, by weight based on the shell weight.
The above and other features and advantages of the invention will become more readily
apparent from the following detailed description taken with the following drawings.
8
BRIEF DESCRIPTION OF THE DRAWINGS
These and other features, aspects, and advantages of the present invention will become better
understood with regard to the following description, appended claims, and accompanying
drawings where:
Figure 1 illustrates a graphical representation of determination of the gelling point
temperature in accordance with one of the examples.
DETAILED DESCRIPTION OF THE INVENTION
The following description includes the preferred best mode of one embodiment of the present
invention. It will be clear from this description of the invention that the invention is not
limited to these illustrated embodiments but that the invention also includes a variety of
modifications and embodiments thereto. Therefore the present description should be seen as
illustrative and not limiting. While the invention is susceptible to various modifications and
alternative constructions, it should be understood, that there is no intention to limit the
invention to the specific form disclosed, but, on the contrary, the invention is to cover all
modifications, alternative constructions, and equivalents falling within the spirit and scope of
the invention as defined in the claims.
In any embodiment described herein, the open-ended terms "comprising," "comprises," and
the like (which are synonymous with "including," "having, "and "characterized by") may be
replaced by the respective partially closed phrases "consisting essentially of," consists
essentially of:" and the like or the respective closed phrases "consisting of," "consists of, the
like.
9
As used herein, the singular forms "a," "an," and "the" designate both the singular and the
plural, unless expressly stated to designate the singular only .
. The term "relative humidity" is used herein to mean the ratio of the actual water vapor
pressure at a given temperature to the vapour pressure that would occur if the air were
saturated at the same temperature.
The term "capsule" herein means a hard capsule consisting of two co-axial, telescopicallyjoined
parts, referred to as body and cap. "Capsule" refers to both empty and filled capsules.
The term "fixed environment" means a particular combination of temperature and relative
humidity which provides excellent results.
The term "solid form" means herein as powder form, and the administration of the
substance(s) may preferably entail the use of a dry powder inhaler.
The term "subject" means a human or animal subject, more preferably a human subject.
The dimensional unit "cps" used herein for measuring viscosity means "centipoises".
In the manufacture of pharmaceuticals, encapsulation refers to a range of dosage formstechniques
used to enclose medicines in a relatively stable shell known as a capsule, allowing
i
them to, for example, be taken orally or be used as suppositories. The two main types of
capsules are; hard-shelled capsules and soft shelled capsule. Fwther, the hard shelled
capsules are typically made using gelatine and contain dry, powdered ingredients or
miniature pellets made by e.g. processes of extrusion or spheronization. These are made in
two halves: a lower-diameter "body" that is filled and then sealed using a higher-diameter
"caprr.
10
Soft-shelled capsules, primarily used for oils and for active ingredients, that are dissolved or
suspended in oil. Both of these classes of capsules are made from aqueous solutions of
gelling agents, such as animal protein (mainly gelatine) or plant polysaccharides or their
derivatives (such as carrageenans and modified forms of starch and cellulose). Other
ingredients can be added to the gelling agent solution including plasticizers such as glycerine
or sorbitol to decrease the capsule's hardness, colouring agents, preservatives, disintegrants,
lubricants and surface treatment.
The present invention envisions an aqueous composition for the manufacture of
hydroxypropyl methyl cellulose hard capsules (HPMC) shells and a method of preparing said
hydroxypropyl methyl cellulose hard capsules obtained therewith.
The composition comprises of 18% - 23% by weight of hydroxypropyl methyl cellulose with
methoxy content of27.0%- 30.0% (w/w); hydroxypropoxy content of7.0%-12% (w/w) and
also provided with a viscosity grade ranging between 3.5 cPs - 6.0 cPs , preferably between
3.8 cPs-5.6 cPs as a 2% weight solution in water at 20° C. The methoxy and
hydroxypropoxy contents in HPMC are expressed according to the USP30-NF25 method for
cellulose derivatives.
Viscosity of the HPMC solution in water is measured by conventional techniques, e.g. as
disclosed in the USP by using a Brookfield viscometer of the Ubbelohde type.
I
I
The aqueous composition further comprises of non animal-derived film-forming polymers (0-
5%); preferably between 0%-2%, gelling system (cations and anions) (1.5-2.5%) preferably
1.5%; at least one inert non-toxic pharmaceutical grade or food grade pigment (0.001 - 1.0%)
and a plasticizer (0- 2%) preferably between 0 - 1% by weight over the total weight of the
composition.
The non animal-derived film-forming polymers are selected from group comprising polyvinyl
alcohol, plant-derived or bacterial-derived film-forming polymers; plant-derived filmforming
polymers may be starch, starch derivatives, cellulose, celluloses derivatives;
bacterial-derived film-forming polymer may be exo-polysaccharides sdected from xanthan,
acetan, gellan, welan, rhamsan, furcelleran, succinoglycan, scleroglycan, schizophyllan,
tamarind gum, curdlan, pullulan, dextran and mixtures thereof.
The gelling system comprises of cations selected from the list comprising K", Na+, Li+,
NH4+, Ca++, Mg++ and mixtures thereof and/or one or more gelling agents selected from
the list comprising guar gum, locust bean gum (carob), carrageenans, tara gum, gum arabic,
ghatti gum, khaya grandifolia gum, tragacanth gum, karaya gum, pectin, arabian (araban),
xanthan, gellan gum, konj ac mannan, galactomannan, funoran, and mixtures thereof.
The composition also comprises of an inert non-toxic pharmaceutical grade or food grade
pigment (0.001- 1.0%) is preferably titanium dioxide and the plasticizer (0-2 %) is preferably
glycerin or propylene glycol included in the aqueous composition by the total weight of said
composition.
HPMC hard capsules obtainable from the aqueous compositions of the invention show good
clarity and transparency. The transmittance measured by UV at 650 nm on the capsule
body(through its double shell layers) is around 80%, identical to gelatin hard capsules.
The aqueous composition of the invention is prepared by dispersing the HPMC and the other
optional ingredients in one or more aqueous solvents, preferably water. The aqueous solvent
can be at a temperature above room temperature, preferably above 70° C. Opt. On completion
of the process of de-bubbling, the dispersion is cooled down below room temperature,
preferably below 20°C., to achieve the solubilisation of the HPMC. The gelling temperature
12
of the aqueous compositions may be determined by a measurement of the viscosity by
progressively heating the composition.
The method of preparation of hydroxypropyl methyl cellulose capsule shells according to a
dip coating process, comprises the steps of; preparing a aqueous composition of a
hydroxypropyl methyl cellulose having methoxy of content 27.0% - 30.0% (w/w);
hydroxypropoxy of content 7.0%-12% (w/w) and with a viscosity grade ranging between 3.8
cPs -5.6 cPs as a 2% weight solution in water at 20° C; wherein concentration of said
hydroxypropyl methyl cellulose generates a viscosity of said composition of 1200 to 3000cPs
measured at a temperature of 20° C, maintaining plurality of pins at temperature ranging
between 23'C- 24°C; dipping said plurality of pins into said aqueous composition to obtain a
dipped composition; maintaining said composition obtained at a temperature ranging between
44°C-46°C below its gelling temperature; withdrawing said dipped plurality of pins from said
aqueous composition, thereby obtaining a film on said dipped plurality of pins; and drying
said film in an oven for a period of time, typically from 60 to 75 minutes on said dipped pins
at a temperature ranging 33'C-35'C to obtain a moulded capsule shell (bodies and caps) on
said plurality of pins; lubricating said plurality of pins by using a de-moulding agent; and
dismantling said capsule shells (bodies and caps) from said lubricated plurality of pins to a
predetermined length and joining said bodies and caps to obtain a pre-locked capsule;
The drying step is implemented to reduce the water content in the capsule shells on the pins.
Generally, the water content in the molded capsule shells is reduced from around 80% to
around 7% by weight, based on the total weight of the molded capsule shells. The drying step
is performed by moving the dipped capsules through a closed chamber of fixed environment
as per the weight/size of the capsule.
13
After the drying there includes two additional steps, in the first step the dipped pins with the
molded capsule shells are subjected to a temperature of 15oC to 20° C. at a RH of 50% to
55% for a time duration ranging between 90-I 80 seconds. The first step is followed by a
second step, wherein the pins are subjected to a temperature of32°C-36°C, at a RH of 30% to
45% for a time duration ranging between 75 to 90 minutes.
The capsule prepared comprises of two co-axial telescopically-joined parts, referred to as
body and cap. The caps and bodies of the capsule comprises of a side wall, an open end and a
closed end region. The length of the side wall of body and cap is generally greater than the
capsule diameter. The only portion of the body which is exposed is the closed end region, and
the closed end region has an outer surface which is of such a configuration as to resist being
gripped, whereby separation of the cap and body is impeded, and wherein when the cap and
body are fully joined in telescopic relationship, the inner side wall of the cap is substantially
totally overlapped by the outer side wall of the body.
The body and the cap of the capsule further include mutual locking means comprising one or
more circumferentially extending ridges and/or grooves, either radially inwardly from an
inner surface of the sidewall of the cap or radially outwardly from an outer surface of the side
wall of the body, as the case may be.
Alternatively, or in addition, the side wall of the other of the cap and body has one or more
circumferentially extending groove extending either radially inwardly from the outer surface
of the body or radially outwardly from the inner surface of the cap, as the case may be, and
engaging a respective ridge.
The capsule shell further includes venting means to permit air to escape from within the
capsule when joined, wherein each circumferentially extending ridge comprises two or more
14
segments so that spaces between the segments act as vents to permit air to escape from within
the capsule when the cap and body are being joined.
It is preferred that the side wall of one of the cap and body has a pair of diametrically
opposed integral indents extending either radially inwardly from the inner surface of the side
wall of the cap or radially outwardly from the outer surface of the side wall of the body, as
the case may be and the diametric spacing of the indents is, in the case less than the outside
diameter of the open end of the body or greater than the inside diameter of the open end of
the cap, such that the body can enter the cap and permit air to escape from within the capsule
when the cap and body are being joined.
For storage and/or transportation purposes, it is preferred that the capsule shell may also
include means for pre-locking the partially joined caps and bodies in a constant
predetermined relative position prior to filling and final joining.
Preferably, bodies have a reduced diameter in the area of their open end in order to avoid
abutment when they are telescopically housed within caps.
Alternatively, or in addition, caps have a reduced diameter in the area of their open end,
thereby resulting in improved engagement between them and the region of the side wall of
the bodies adjacent the closed end region of the bodies, as further resistance to tampering.
The. HPMC shell prepared comprises of 88% - 92% of HPMC (methoxy content of 27.0-
30.0% (w/w), a hydroxypropoxy content of7.0-12% (w/w) and a viscosity of3.8-5.6 cPs as a
2% weight solution in water at 20"C) ; I%- 3% non animal derived film-forming polymers,
preferably between 1.5% - 2.5% ; I% to 8% water, preferably between 7% - 5%,; at least one
plasticizer between 0-5%; at least one antibacterial agent between 0- 0.5%; at least one
flavouring agent between 0- I%, by weight based on the shell weight and wherein the
viscosity is measured according to the USP method for cellulose derivatives.
15
The invention also relates to the use of hydroxypropyl methyl cellulose hard capsule for the
manufacture of pharmaceutical dosage forms suitable for the administration to a subject of
pharmaceutical substances in solid form, wherein capsules comprise of 0.00 I g - 2.0g of
active ingredient, optionally mixed with one or more pharmaceutically acceptable excipients.
It can also be used for the manufacture of tamper-proof phannaceutical dosage forms. In one
embodiment, the HPMC hard capsule can be used in the context of dry powder inhalers (also
commonly know by the acronym DP!s. The HPMC hard capsules thus produced has reduced
stickiness of the internal surface of caps and bodies side walls due for example to a reduced
amount of de-moulding agent required in capsule manufacturing process.
Hereinafter, the present invention will be described in further detail by examples. It will
however be obvious to a person skilled in the art that these examples are provided for
illustrative purpose only and are not construed to limit the scope of the present invention.
EXAMPLE 1
Aqueous Composition for the Manufacture of Hydroxypropyl Methyl Cellulose Hard
Capsules
A 5 kg composition of 22% HPMC type 2910 (methoxy content 28.7%, hydroxypropoxy
content 8.7%) of 4.4 cPs viscosity at 2% concentration (w/w) was prepared as follows: The
HPMC powder was dispersed into hot water containing Potassium Acetate 0.5 % w/w of
I I
HPMC as co-gelling agent at 75°C under stirring, after complete dispersion of the powder,
the temperature was kept at 75°C, under very gentle stirring for de-foaming of the dispersion.
Then the dispersion was cooled down to 20°C under gentle stirring for obtaining dissolution
of the HPMC. After keeping the composition for more than 30 minutes at 20°C, it was
gradually further raised to 40'C under gentle stirring just below the gelling point of the
composition.
16
To the above 2.00% w/v solution of a gelling agent Carrageenan was added under stirring, in
quantity 2.5% w/w of Carrageenan to HPMC. After a homogenous dispersion was ready it
was homogenized at high speed stirring for I hour. This homogenised composition was kept
under gentle stirring for de-foaming of the composition. A dipping composition thus ready
for use in capsule manufacturing was o~tained having viscosity of I 400 cPs to I 600 cPs at
HPMC composition gelling temperature was determined by viscosity measurement by
progressively heating the composition. The gelling temperature found was 47°C as depicted
in Figure 1.
GELLING POINT TEMP.
18100
16100
f. 14100
il it 12100
10100
8100
6100
4100
2100
A
/""
100
27 29 31 33 35 37 39 41 43 45 47 49
Figure 1
The composition prepared in example 1 was poured into the dipping dish of a pilot
equipment of hard capsule manufacturing. The dip pins of size 0 were maintained at 24°C,
while the dipping composition was maintained at 45°C. At this temperature, the viscosity of
the dipping composition was I 800 cPs. Capsules of size 0 were manufactured by the
conventional dipping process. After the dipping, the capsules were initially dried at I ST in a
17
closed chamber for 2 minutes before drying in an oven tunnel with hot dehumidified air at
34'C and humidity at 40% for 80 minutes.
It was observed that the capsules obtained were of high quality, good and of standardized
dimension (the top wall thickness is >120 Jlm), high transparency (similar to hard gelatine
capsules), excellent dissolution and mechanical performance.
EXAMPLE2
The composition prepared in example 1 was poured into the dipping dish of a pilot equipment
of hard capsule manufacturing. The dip pins of size 0 were maintained at 20'C while the
dipping composition was maintained at 40°C. At this temperature, the viscosity of the
dipping composition was 1400 cPs. Capsules of size 0 are manufactured by the conventional
dipping process. After the dipping, the capsules were dried in an oven tunnel with hot
dehumidified air at 34 'C and humidity at 40% for 75 minutes. The gelling on the pins after
dipping was not optimal to obtain commercially acceptable capsules. Solution partially flew
down the pin during drying, leading to the top wall thickness less than 50 Jlm.
With parameters defined as per the above example, the capsules obtained thus were not of
acceptable quality.
EXAMPLE3
Herein, Example 1 was re-run but with initial 2 min drying temperature of 24 'C and an oven
tunnel parameters maintained same. Solution partially flew down the pin during drying,
leading to the top wall thickness less than 50 Jlm.
With parameters defined as per the above example, the capsules obtained thus were not of
acceptable quality.
18
EXAMPLE4
Example I was re-run with an oven tunnel temperature raised to 36oC keeping all other
parameters same as EXAMPLE l. The resultant dried capsules showed slight haziness.
With parameters defined as per the above example, the capsules obtained thus were not of
acceptable quality.
EXAMPLES
Example l was re-run, with dipping composition viscosity maintained at 1000 cPs and rest of
the parameters same as EXAMPLE l. The solution practically flew down the pin during
drying owing Low viscosity of the dipping composition, leaving no significant Mass on the
pins.
With parameters defined as per the above example, the capsules obtained thus were not of
acceptable quality.
The mechanical properties of the capsules of example l were tested under stress conditions as
follows:
A stainless steel cylinder weighing l 00 g was allowed to fall from a height of 8 em onto
empty capsules one by one. The percentage of broken capsules was reported hereunder in
Table 1.
Table I
Storage conditions RH % Capsules of example 1 Gelatin capsules
25 0 7
----------------- ·----
30 0 4
40 0 0
50 0 0
19
I
I I
It was observed that capsules of EXAMPLE I do not exhibit any brittleness even at
extremely low relative humidity.
Disintegration Test of these capsules of EXAMPLE l was performed as per Pharmacopoeia
and capsules disintegrate within 6 minutes to 9 minutes, which were well within
Pharmacopoeial limit ofNMT 15 minutes .
. EXAMPLE6
In Vitro Dissolution Performance & Stability Study Results of the Capsules of Example
1.
In Vitro, Dissolution Performance of Hard Cellulose Capsule Shells, with Acetaminophen
Active Pharmaceutical Ingredient, as per USP Monograph was performed.
Contents:-
Dissolution Time (in Min.) % Acetaminophen LIMIT
Medium Dissolved
15 Min. 25%
pH 6.8 30 Min. 56% Not Less Than 80
Potassium 45 Min. 75% % Dissolved.
phosphate 60Min. 85%
75 Min. 91%
Accelerated Stability:
Product: HARD CELLULOSE CAPSULE SHELLS
Batch No. : Trail Batch I
Batch Size: 1.00 Lakh
Mfg. Date: SEPTEMBER- 2016
Temperature of Storage: 40'C ± 2'C
20
I I
I
I
Humidity of Storage: 75% ± 5% RH
Containers I Packing: Samples kept in translucent polyethylene bag closed by zip lock, the
bags covered with EPS sheets and the EPS Sheets covered by 5 ply corrugated boxes.
--·-
RESULTS
TESTS Specification
Initial 1 Month 2 Months 3 Months 6 Months
Moisture 3.00-9.00 7.25 %w/w 7.37% w/w 7.41% w/w 7.45% w/w 7.55 %w/w
%w/w
Brittleness Not Not Brittle Not Brittle Not Brittle Not Brittle Not Brittle
Brittleness
Deformation Not Not Deform Not Deform Not Deform Not Deform Not Deform
Deformed
Disintegration NMT 15 7.40 Min. 7.50Min. 7.55 Min. 8.05 Min. 8.10 Min.
time Minutes
-·----
Total Aerobic NMT500 210 cfu/gm 200 cfu/gm 200 cfu/gm 210 cfu/gm 220 cfu/gln-
Count cfu/gm
E. coli Absent/gm Absent/gm Absent/gm Absent/gm Absent/gm Absent/gm
Staphylococcus Absent/gm Absent/gm Absent/gm Absent/g~n Absent/g~n Absent/g~n
au reus
Pseudomonas Absent/gm Absent/gm Absent/gm Absent/gm Absent/gm Absent/gm
aeruginosa
Salmonella Absent/IOgm Absent/1 Ogm Absent/IOgm Absent/IOgm Absent/1 Ogm Absent/1 Ogm
Shigella A bsent/1 Ogm Absent/1 Ogm Absent/! Ogm Absent/1 Ogm Absent/ I Ogm Absent/1 Ogm
As per the various tests conducted, it was observed that the Stability was well within the
acceptable limit up to 6 months of Accelerated study.
Real Time Stability:
21
Pr·odnct: HARD CELLULOSE CAPSULE SHELLS
Batch No. : Trail Batch I
Batch Size: 1.00 Lakh
Mfg. Date: SEPTEMBER- 2016
Temperature of Storage: 25"C ±2"C
Humidity of Storage: 60% ± 5% RH
Containers I Packing: Samples kept in translucent polyethylene bag closed by zip lock, the
bags covered with EPS sheets and the EPS Sheets covered by 5 ply corrugated boxes.
Protocol Reference Doc.: SP/HPMC/001
RESULTS
TESTS Specification 9 12
Initial 3 Month 6 Months
Months Months
Moisture 3.00-9.00 7.25 %w/w 7.28%w/w 7.31 %w/w - -
%w/w
Brittleness Not Not Brittle Not Brittle Not Brittle - -
Brittleness
Deformation Not Not Deform Not Deform Not Deform - -
Deformed
Disintegration NMT 15 7.40 Min. 7.40 Min. 7.45 Min. - -
time Minutes
Total Aerobic NMT 500 210 cfu/gm 210 cfu/gm 210 cfu/gm - -
Count cfu/gm
22
I·
I
E.coli Absent/gm Absent/gm Absent/gm Absent/gm -
Staphylococcus Absent/gm Absent/gm Absent/gm Absent/gm -
au reus
Pseudomonas Absent/gm Absent/gm Absent/gm Absent/gm -
aeruginosa
Salmonella Absent/ I Ogm Absent/! Ogm Absent/! Ogm Absent/1 Ogm -
Shigella Absent/! Ogm Absent/! Ogm Absent/1 Ogm Absent/1 Ogm -
The Stability was well within the acceptable limit upto six months of Real Time Stability
study.
In alternative embodiments of the present invention, suitable aqueous compositions can be
obtained by blending HPMCs of same type but different viscosity grade.
While the present invention has been described above according to its preferred
embodiments, it can be modified within the spirit and scope of this disclosure. This
application is therefore intended to cover any variations, uses, or adaptations of the present
invention using the general principles disclosed herein. Further, the application is intended to
cover such departures from the present disclosure as come within the known or customary
practice in the art to which this present invention pertains and which fall within the limits of

We Claim:
1. An improved composition for the manufacture of hydroxypropyl methyl cellulose hard
capsules (HPMC) shells, comprising;
- hydroxypropyl methyl cellulose in the range 18 % - 23 % by weight, wherein said cellulose
contains methoxy in the range 27.0%- 30.0% (w/w) and hydroxypropoxy in the range 7.0
%-12% (w/w);
-plurality of non animal-derived film-forming polymers in the range 0-5 %;
-a gelling system containing cations and gelling agents in the range 1.5-2.5 %;
- at least one inert non-toxic pharmaceutical grade pigment in the range 0.00 I - 1.0 %; and
- at least one plasticizer in the range 0- 2 % by weight over the total weight of said
composition.
2. An improved composition for the manufacture of hydroxypropyl methyl cellulose hard
capsules (HPMC) shells as claimed in Claim I, wherein said non animal-derived filmforming
polymers is preferably present in the range 0% - 2%; said gelling system is
preferably 1.5%; said plasticizer is preferably present in the range 0 - I% by weight over the
total weight of said composition.
3. An improved composition for the manufacture of hydroxypropyl methyl cellulose hard
capsules (HPMC) shells as claimed in Claim 1, wherein said composition comprises of a
viscosity grade of 3.8 cPs -5.6 cPs as a 2% weight solution in water at 20° C and said
viscosity grade is measured according to the USP30-NF25 method for cellulose derivatives.
24
4. An improved composition for the manufacture of hydroxypropyl methyl cellulose hard
capsules (HPMC) shells as claimed in Claim I, wherein said non animal-derived filmforming
polymers are selected from group comprising polyvinyl alcohol, plant-derived or
bacterial-derived film-forming polymers.
5. An improved composition for the manufacture of hydroxypropyl methyl cellulose hard
capsules (HPMC) shells as claimed in Claim I, wherein said plant-derived film- forming
polymers are preferably starch, starch derivatives, cellulose, cell uloses derivatives,
6. An improved composition for the manufacture of hydroxypropyl methyl cellulose hard
capsules (HPMC) shells as claimed in Claim I, wherein said bacterial-derived film-forming
polymers are preferably exo-polysaccharides selected from xanthan, acetan, gellan, welan,
rhamsan, furcelleran, succinoglycan, scleroglycan, schizophyllan, tamarind gum, curdlan,
pull ulan, dextran and mixtures thereof.
7. An improved composition for the manufacture of hydroxypropyl methyl cellulose hard
capsules (HPMC) shells as claimed in Claim 1 , wherein said gelling system comprises of
cations selected from the list comprising K +, Na+, Li+, NH4+, Ca++, Mg++ and mixtures
thereof and one or more gelling agents selected from the list comprising guar gum, locust
bean gum(carob), carrageenans, tara gum, gum arabic, ghatti gum, khaya grandifolia gum,
tragacanth gum, karaya gum, pectin, arabian (araban), xanthan, gellan gum, konj ac mannan,
galactomannan, funoran, and mixtures thereof.
8. An improved composition for the manufacture of hydroxypropyl methyl cellulose hard
capsules (HPMC) shells as claimed in Claim I, wherein said inert non-toxic pharmaceutical
grade pigment is preferably titanium dioxide.
25
9. An improved composition for the manufacture of hydroxypropyl methyl cellulose hard
capsules (HPMC) shells as claimed in Claim I, wherein said plasticizer is preferably glycerin
or propylene glycol included in said composition by the total weight of said composition.
I 0. The method of preparation of hydroxypropyl methyl cellulose capsule shells, comprising
the steps of;
a) preparing an aqueous composition of a hydroxypropyl methyl cellulose having
methoxy of content 27.0%-30.0% (w/w); hydroxypropoxy of content 7.0%-12%
(w/w) and with a viscosity grade ranging between 3.8 cPs -5.6 cPs as a 2% weight
solution in water at 20° C;
b) pre-heating plurality of pins of a predefined size at temperature ranging between
c) dipping said plurality of pins into said aqueous composition to obtain a dipped
composition;
d) maintaining said composition obtained in step (c) at a temperature ranging
between 44°C-46°C below its gelling temperature;
e) withdrawing said dipped plurality of pins trom said aqueous composition, thereby
obtaining a film on said dipped plurality of pins; and
t) initially drying at pre-drying stage for 2 minutes at J5'C- 20'C and Rh of 50%-
55%.
26
g) drying said film of step (e) in an oven for a period oftime, typically from 75 to 90
minutes on said dipped pins at a temperature ranging 33°C-35"C to obtain a
moulded capsule shell (bodies and caps) on said plurality of pins;
h) dismantling said capsule shells (bodies and caps) from said plurality of pins and
trimming to a predetermined length; and
i) joining said bodies and caps to obtain a pre-locked capsule;
j) lubricating said plurality of pins by using a de-moulding agent;
11. The method of preparation ofhydroxypropyl methyl cellulose capsule shells as claimed in
Claim 10, wherein step (f) comprises of a first additional step, subjecting said plurality of
pins to a temperature of 15oC to 20° C. and relative humidity of 50% to 55% for a time
duration ranging between 90-180 seconds.
12. The method of preparation ofhydroxypropyl methyl cellulose capsule shells as claimed in
Claim 10, wherein step (f) comprises of a second additional step, subjecting said plurality of
pins to a temperature of 32oC-36°C and relative humidity of 30% to 45% for a time duration
ranging between 75 to 90 minutes.
13. The method of preparation ofhydroxypropyl methyl cellulose capsule shells as claimed in
Claim I 0, wherein said capsule comprises of a cap and a body telescopically joined together
and said cap and body fwiher comprises of a side wall, an open end and a closed end region,
mutual locking means comprising one or more circumferentially extending ridges and/or
grooves either radially inwardly or radially outwardly and a venting means to permit air to
escape from within the capsule when joined.
27

14. The method of preparation of hydroxypropyl methyl cellulose capsule shells as claimed in
Claim l 0, wherein said capsule shell prepared comprises 88% - 92% of HPMC (methoxy
content of27.0-30.0% (w/w), a hydroxypropoxy content of7.0-l2% (w/w) and a viscosity of
3.8-5.6 cPs as a 2% weight solution in water at 20oC); I% - 3% non animal derived filmforming
polymers ; I% to 8% water; at least one plasticizer between 0-5%; at least one
antibacterial agent between 0- 0.5% and at least one flavouring agent between 0- I%.