U.S. patent application number 17/090192 was filed with the patent office on 2021-02-25 for advanced processing of absorbable poly(p-dioxanone) containing high level of p-dioxanone monomer.
The applicant listed for this patent is Ethicon, Inc.. Invention is credited to Sasa Andjelic, Brian M. Kelly, Marc Wisnudel.
Application Number | 20210054141 17/090192 |
Document ID | / |
Family ID | 1000005199076 |
Filed Date | 2021-02-25 |
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United States Patent
Application |
20210054141 |
Kind Code |
A1 |
Andjelic; Sasa ; et
al. |
February 25, 2021 |
Advanced Processing of Absorbable Poly(p-dioxanone) Containing High
Level of p-Dioxanone Monomer
Abstract
The present invention is directed methods of making absorbable
poly(p-dioxanone) pellets by melt polymerization of p-dioxanone
conducted in a single reactor with a temperature regulator by
charging a melt reactor with a mixture of p-dioxanone (PDO)
monomer, initiator, catalyst, and optionally a dye; melt
polymerizing the mixture in the melt reactor with sufficient
agitation of the mixture to allow complete mixing of the monomer
and for sufficient time to form a PDO polymer product having an
unreacted PDO monomer content of at least 65 mole percent; placing
the PDO polymer product under a vacuum to remove at least portion
of unreacted PDO; discharging the PDO polymer product from the melt
reactor directly into an in-line, underwater pelletizer to produce
undried PDO pellets, collecting the undried PDO pellets, and
storing the collected PDO pellets in the freezer or a vacuum
chamber prior to drying.
Inventors: |
Andjelic; Sasa; (Nanuet,
NY) ; Kelly; Brian M.; (Ringoes, NJ) ;
Wisnudel; Marc; (Millburn, NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Ethicon, Inc. |
Somerville |
NJ |
US |
|
|
Family ID: |
1000005199076 |
Appl. No.: |
17/090192 |
Filed: |
November 5, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16202454 |
Nov 28, 2018 |
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17090192 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C08J 3/12 20130101; C08G
63/785 20130101; C08G 63/66 20130101; C08G 63/85 20130101; C08K
5/18 20130101 |
International
Class: |
C08G 63/66 20060101
C08G063/66; C08G 63/78 20060101 C08G063/78; C08G 63/85 20060101
C08G063/85; C08J 3/12 20060101 C08J003/12; C08K 5/18 20060101
C08K005/18 |
Claims
1. A polymeric filament extruded from a PDO pellet made in
accordance with the method of making absorbable poly(p-dioxanone)
pellets by melt polymerization of p-dioxanone conducted in a single
reactor with a temperature regulator, and comprising the steps of:
i. charging a melt reactor with a mixture of p-dioxanone (PDO)
monomer, initiator, catalyst, and optionally a dye; ii. melt
polymerizing the mixture at a reaction temperature of between
95.degree. C. and 145.degree. C. in the melt reactor with
sufficient agitation of the mixture to allow complete mixing of the
monomer and for sufficient time to form a PDO polymer product of at
least 65 mole percent having an unreacted PDO monomer content; iii.
placing the PDO polymer product under a vacuum for about 60 to 180
minutes to remove at least portion of unreacted PDO, as measured by
monomer content; iv. discharging the PDO polymer product from the
melt reactor directly into an in-line, underwater pelletizer to
produce undried PDO pellets, v. collecting the undried PDO pellets,
and vi. storing the collected PDO pellets in the freezer or a
vacuum chamber.
2. A polymeric filament made in accordance with the method of claim
1, wherein the melt polymerization of PDO monomer is conducted in a
single reactor in the presence of a monofunctional initiator at an
initiator concentration of between 500:1 to 2,000:1 (mole of
monomer: mole of initiator), and in the presence of a catalyst in
the total amount of 30,000:1 to 300,000:1 (moles of monomer: moles
of catalyst), for total reaction time of between 4 hours and 16
hours.
3. A polymeric filament made in accordance with the method of claim
2, wherein the monofunctional initiator is dodecanol.
4. A polymeric filament made in accordance with the method of claim
2, wherein the catalyst is stannous octoate.
5. A polymeric filament made in accordance with the method of claim
2, wherein the dye is D&C Violet Number 2 in a dye
concentration of between 0.01 and 0.2 weight percentage.
6. A polymeric filament made in accordance with the method of claim
1, wherein the unreacted PDO monomer content after step (iii) is
between about 15 mole percent to about 35 mole percent and wherein
pelletization is conducted by the underwater pelletizer having a
pump and a cutter under following conditions: a. Setting the melt
reactor to an operating temperature of from 95.degree. C. to
130.degree. C.; b. Initially setting the melt rector agitator at a
rotational speed of between 2 RPM to 6 RPM or from about 20-40% of
the rotational speed for step (ii); c. Initially setting the pump
speed in the pelletizer at about 5 RPM to about 7 RPM, and
gradually increasing the pump speed to the range between 10 RPM and
15 RPM; d. Setting the pelletizer to a die temperature of about
100.degree. C. to 140.degree. C.; e. Setting the cutter to a
rotational speed of between about 2,000 and 3,600 RPM.
7. A polymeric filament made in accordance with the method of claim
1 further comprising the step of drying the poly(p-dioxanone)
pellets.
8. A polymeric filament made in accordance with the method of claim
7 wherein the poly(p-dioxanone) pellets are dried using a fluidized
bed drying apparatus.
9. A polymeric filament made in accordance with the method of claim
7, wherein the drying is conducted using tumble dryers, equipped
with vacuum and/or heating capabilities, including the steps of: a.
Transferring undried poly(p-dioxanone) pellets having an unreacted
p-dioxanone monomer content of between about 15 mole percent to
about 35 mole percent into a tumble drier, b. applying a vacuum in
the tumble drier at room temperature and reducing the moisture
level in poly(p-dioxanone) pellets to less than 100 parts per
million, as measured by a moisture analyzer; c. setting the drier
temperature to a starting drying temperature of about 55.degree. C.
and maintaining the heat and vacuum for about two to six hours; d.
setting the drier temperature to an intermediate drying temperature
of about 75.degree. C. and maintaining the heat and vacuum for
about two to six hours; e. setting the drier temperature to a final
drying temperature from about 85.degree. C. to 95.degree. C. and
maintaining the heat and vacuum for about 16 to 32 hours; and f.
collecting the dried poly(p-dioxanone) pellets.
10. The polymeric filament made in accordance with the method of
claim 9, wherein the dried poly(p-dioxanone) pellets contain less
than 4 mole % of unreacted PDO monomer at the end of drying
process.
11. The polymeric filament made in accordance with the method of
claim 9, wherein the dried poly(p-dioxanone) pellets have an
inherent viscosity (IV) as measured in hexafluoroisopropanol at
25.degree. C. and at a concentration of 0.10 g/dL of greater than
1.2 dl/g.
12. The polymeric filament made in accordance with the method of
claim 9, wherein the dried poly(p-dioxanone) pellets have a weight
average molecular weight (Mw) greater than 50,000 Daltons, as
measured by gel permeation chromatography.
13. The polymeric filament made in accordance with the method of
claim 9, wherein the dried poly(p-dioxanone) pellets have a
crystallinity level greater than 45% as measured by Wide Angle
X-ray Diffraction (WAXD) after being subjected to a heat treatment
between about 60.degree. C. and 90.degree. C. for at least six
hours.
Description
FIELD OF THE INVENTION
[0001] This invention describes novel methods in processing melt
polymerized poly(p-dioxanone) resin containing high monomer levels,
such as from 15-35 mole %. These methods may include a use of
underwater pelletization during melt polymerization of p-dioxanone,
followed by selected drying steps to threat such formed
pellets.
BACKGROUND OF THE INVENTION
[0002] Problems to be solved: Discharging a low glass transition
temperature polymer from a reactor with high level of residual
monomer via pelletization process represents an enormous technical
challenge. This challenge is present because such fully amorphous
resins are likely to be too soft prior to pelletization, having
high concentration of liquid monomer residuals. The second big
hurdle is that majority of such polymers, for instance a
poly(p-dioxanone) resin loaded with high monomer content is
moisture sensitive, causing a significant degradation that can
occur prior and during the drying procedure (removal of monomer by
a heating step under vacuum).
[0003] The homopolymer and copolymers of p-dioxanone are attracting
increased interest in the medical device and pharmaceutical fields
because of their low toxicity, softness, and flexibility.
Poly(p-dioxanone) (PDS) was first suggested as an absorbable
polymer by Doddi et al. [U.S. Pat. No. 4,052,988A "Synthetic
absorbable surgical devices of poly-dioxanone" by Namassivaya
Doddi; Charles C. Versfelt, and David Wasserman (Ethicon, Inc.)].
By the early 1980s, the homopolymer was used to form of a
monofilament surgical suture. Since then, many p-dioxanone
copolymers have been described [Bezwada, R. S.; Jamiolkowski, D.
D.; Cooper, K. In Handbook of Biodegradable Polymers; Domb, A. J.;
Kost, J.; Wiseman, D. M., Eds.; Harwood Academic: Singapore, 1997;
Chapter 2.]. Monofilaments based on a copolymer with trimethylene
carbonate, glycolide, and p-dioxanone monomer have been cleared by
the U.S. Food and Drug Administration and are presently offered for
sale [U.S. Pat. No. 5,403,347 Roby, M.; Bennett, S. L.; Liu, C. K.
(United States Surgical Corp.)].
[0004] PDS, with its low glass-transition temperature
(Tg=-10.degree. C.), is inherently soft and flexible. The low value
of Tg also allows this crystallizable material to exhibit these
properties at room temperature. Thus, besides being well suited for
surgical monofilaments, it can be injection-molded into a number of
non-filamentous surgical devices such as clips (ABSOLOK.TM. and
LAPRA-TY.TM.), and fasteners (Mitek Meniscal Repair System). These
surgical articles take full advantage of the general toughness
exhibited by this family.
[0005] A standard procedure of polymerizing p-dioxanone involves an
initial short liquid (melt) phase in a reactor, followed by an
extended solid phase in a curing oven typically set at the
temperatures between 65.degree. C. to 85.degree. C. [see U.S. Pat.
Nos. 4,052,988, 5,717,059, and 6,448,367B1]. For instance, U.S.
Pat. No. 4,052,988 "Synthetic absorbable surgical devices of
poly-dioxanone" by Namassivaya Doddi; Charles C. Versfelt, and
David Wasserman (Ethicon, Inc.) described the synthesis of
absorbable poly-dioxanone homopolymers starting in melt, and
finishes utilizing solid state curing step at 80.degree. C. The
resin is used in subsequent fiber production for use as surgical
sutures. The use of solid state stage is because formed
poly(p-dioxanone) is in thermodynamic equilibrium with its
p-dioxanone monomer, causing the shift of monomer regeneration at
higher reaction temperature. Lowering the reaction temperature to
the range between 65.degree. C. and 85.degree. C., the resin
solidifies or crystallizes, which helps to advance the
polymerization (monomer conversion). However, due to diffusional
difficulties in the solid state, the reaction kinetics are very
slow and require several days to achieve high conversion. Oven
cured poly(p-dioxanone) typically has about 5-15 mole % of
unreacted p-dioxanone monomer before a drying step.
[0006] U.S. Pat. No. 5,717,059 (Shell Oil Company, Houston Tex.)
describes the method for preparing poly(p-dioxanone) by first,
producing a reaction product mixture of molten poly(p-dioxanone)
and unreacted p-dioxanone, and then solidifying that mixture into a
plurality of solid particles. The particles are then transferred
into a separator vessel, where under reduced pressure and
temperature are swept by an inert gas. This procedure separates the
polymer from monomer, which is being recycled in a continues
process. The inventors also pointed out the problems of monomer
removal directly from the poly(p-dioxanone) by applying 2.5-hour
vacuum to remove unreacted monomer. The weight average molecular
weight of the polymer after monomer removal dropped dramatically by
41% of the molecular weight of the polymer prior to vacuum stage.
This was explained by a shift in chemical equilibrium as the
monomer was removed from the polymer/monomer mixture.
[0007] U.S. Pat. No. 5,652,331 ("Method for preparing
poly(p-dioxanone) polymer" Shell Oil Company, Houston Tex.) tried
to address the problem of monomer removal in the poly(p-dioxanone)
melt by adding to product mixture a cyclic anhydride to form
end-capped poly(p-dioxanone). The reaction continues by applying
the vacuum while exposing the mixture to temperature range of about
50 to about 150.degree. C. The final step involves recovering the
end-capped poly(p-dioxanone). The inventors provided data indicated
difficulties of removing unreacted monomer from the melt because of
the tendency of the polymer to degrade significantly, or the loss
of molecular weight as the monomer is removed. However, inducing
the chemical reaction of poly(p-dioxanone) with cyclic anhydride,
the formed product withstands chemical degradation after the
monomer removal.
[0008] Finally, melt processing of polymers, including underwater
pelletization is described in multiple studies [U.S. Pat. No.
5,844,067A ("A process for producing absorbable segmented
copolymers of aliphatic polyesters with a uniform sequence
distribution"), U.S. Pat. No. 9,873,790B1 ("An absorbable
semi-crystalline polymer blend composition"), U.S. Pat. No.
9,862,826B2 ("Halogen-free polymer blend" describing melt
pelletization of polyether block amide)]. However, none of these
references describe the use of underwater pelletization on
slow-crystallizing, absorbable polymers having glass transition
below 20.degree. C., particularly underwater pelletization of
poly(p-dioxanone) that is additionally moisture sensitive and prone
to fast degradation.
SUMMARY OF THE INVENTION
[0009] The present invention addresses many of the problems and
shortcomings noted above for the manufacture of
poly(p-dioxanone).
Solutions to the problems: Several innovative steps are introduced
during melt polymerization of poly(p-dioxanone) that allows
successful pelletization of the resin with as high as 35 mole % of
residual monomer. These include, optimal time and temperature
profile for reactor-only PDO polymerization, a vacuum stage prior
to an underwater pelletization, and the use of improved processing
conditions during the pelletization. In addition, a novel drying
procedure has been proposed to limit degradation of the
moisture-sensitive undried poly(p-dioxanone) pellets.
[0010] The present invention is directed methods of making
absorbable poly(p-dioxanone) pellets by melt polymerization of
p-dioxanone conducted in a single reactor with a temperature
regulator by charging a melt reactor with a mixture of p-dioxanone
(PDO) monomer, initiator, catalyst, and optionally a dye; melt
polymerizing the mixture in the melt reactor with sufficient
agitation of the mixture to allow complete mixing of the monomer
and for sufficient time to form a PDO polymer product having an
unreacted PDO monomer content of at least 65 mole percent; placing
the PDO polymer product under a vacuum to remove at least portion
of unreacted PDO; discharging the PDO polymer product from the melt
reactor directly into an in-line, underwater pelletizer to produce
undried PDO pellets, collecting the undried PDO pellets, and
storing the collected PDO pellets in the freezer or a vacuum
chamber prior to drying.
[0011] The melt polymerization of PDO monomer can be conducted in a
single reactor in the presence of a monofunctional initiator at an
initiator concentration of between 500:1 to 2,000:1 (mole of
monomer: mole of initiator), and in the presence of a catalyst in
the total amount of 30,000:1 to 300,000:1 (moles of monomer: moles
of catalyst), for total reaction time of between 4 hours and 16
hours. The monofunctional initiator can be dodecanol. The catalyst
can be stannous octoate. The dye, when present, can be D&C
Violet Number 2 in a dye concentration of between 0.01 and 0.2
weight percentage.
[0012] The unreacted PDO monomer content of an intermediate product
can be between about 15 mole percent to about 35 mole percent. The
pelletization step can be conducted by the underwater pelletizer
wherein the melt reactor operates at a temperature of from
95.degree. C. to 130.degree. C.; the melt rector agitator operates
at a rotational speed of between 2 RPM to 6 RPM or from about
20-40% of the rotational speed of the preceding step. The pump
speed in the pelletizer can operate at about 5 RPM to about 7 RPM,
and then gradually increased to the range between 10 RPM and 15
RPM. The pelletizer can operate at a die temperature of about
100.degree. C. to 140.degree. C. The cutter can operate at a
rotational speed of between about 2,000 and 3,600 RPM.
[0013] The methods described above can further include the step of
drying the poly(p-dioxanone) pellets. The poly(p-dioxanone) pellets
can be dried using a fluidized bed drying apparatus. Alternatively,
the drying can be conducted using tumble dryers, equipped with
vacuum and/or heating capabilities, including the steps of:
transferring undried poly(p-dioxanone) pellets having an unreacted
p-dioxanone monomer content of between about 15 mole percent to
about 35 mole percent into a tumble drier; applying a vacuum in the
tumble drier at room temperature and reducing the moisture level in
poly(p-dioxanone) pellets to less than 100 parts per million, as
measured by a moisture analyzer; setting the drier temperature to a
starting drying temperature of about 55.degree. C. and maintaining
the heat and vacuum for about two to six hours; setting the drier
temperature to an intermediate drying temperature of about
75.degree. C. and maintaining the heat and vacuum for about two to
six hours; setting the drier temperature to a final drying
temperature from about 85.degree. C. to 95.degree. C. and
maintaining the heat and vacuum for about 16 to 32 hours; and
collecting the dried poly(p-dioxanone) pellets.
[0014] The dried poly(p-dioxanone) pellets can contain less than 4%
of unreacted PDO monomer at the end of drying process, and/or have
an inherent viscosity (IV) as measured in hexafluoroisopropanol at
25.degree. C. and at a concentration of 0.10 g/dL of greater than
1.2 dl/g, and/or a weight average molecular weight (Mw) greater
than 50,000 Daltons, as measured by gel permeation chromatography,
and/or a crystallinity level greater than 45% as measured by Wide
Angle X-ray Diffraction (WAXD) after being subjected to a heat
treatment between about 60.degree. C. and 90.degree. C. for at
least six hours.
BRIEF DESCRIPTION OF THE DRAWINGS
[0015] FIG. 1 is a schematic of the prior art poly(p-dioxanone)
synthesis route.
[0016] FIG. 2 is a schematic of the improved poly(p-dioxanone)
synthesis route.
[0017] FIG. 3 illustrates the reaction kinetics from Example 1.
[0018] FIG. 4 illustrates the reaction kinetics from Example 4.
DETAILED DESCRIPTION OF INVENTION
[0019] In this section, we will describe inherent difficulties of
p-dioxanone (PDO) polymerization by melt synthesis. During melt
polymerization of PDO, the polymer yield is very low due to
thermodynamic equilibrium of polymer and monomer, which favors the
monomer generation at higher processing temperature. Because of
this, a standard procedure of making poly(p-dioxanone) resin
includes a very short reactor melt synthesis step, followed by
extended solid state polymerization at low temperature (typically
around 80.degree. C.) in a curing oven. After about 4-5 days of
solid state polymerization, the solidified/crystallized
poly(p-dioxanone) packs are ground and sieved prior to the final
drying step (monomer removal by vacuum and heat).
[0020] Potential disadvantages of the existing methods for
solid-state polymerization are very long cycle time, questionable
sample uniformity of cured solid-state packs due to diffusion
difficulties, and a presence of fines as a byproduct of a grinding
operations. Fines may negatively affect extrusion process, since
they melt much earlier than the rest of larger particles.
[0021] The present invention describes the novel methods of
producing poly(p-dioxanone) resin, or other absorbable polymers
having glass transition temperature below 20.degree. C. that
contain high monomer content, preferably in the range from about 15
mole % to about 35 mole %. The melt polymerization is carried out
entirely in a single reactor, followed by underwater palletization.
Applicants unexpectedly discovered that such soft polymer resins
with high liquid content can be successfully pelletized using a
specific set of processing conditions described in this invention.
In addition, Applicants discovered that the resulting undried
pellets containing between about 15 mole % to about 35 mole %
unreacted PDO monomer are extremely sensitive to the moisture in an
air, causing the pellets/resin to degrade (loose molecular weight)
in an accelerated pace. Therefore, several new steps prior and
during the drying stage are essential to limit the molecular weight
loss of pelletized polymers.
[0022] The inventive methods described herein of melt polymerizing
p-dioxanone, followed by one-step discharge via underwater
pelletization provide following important benefits: [0023] 1.
Reduction of the cycle time for a minimum of 96 hours, by
eliminating oven curing and grinding/sieving operations; [0024] 2.
Production of chemically and morphologically uniform resin
particles, i.e. pellets, allows higher lot-to-lot consistency;
[0025] 3. Elimination of fines and resulting production of
particles/pellets with the same form and size; this improves
robustness of the extrusion process with more consistent diameter;
[0026] 4. Reduction of catalyst requirements; lower catalyst may
aid in resin's stability during melt processing; and [0027] 5.
Reduction in the cost of production.
[0028] The melt blend can be prepared in stainless steel reactor,
which is customarily equipped with an oil jacket and blades for
agitation. PDO monomer is added along with an initiator and
catalyst, and optionally a colorant, such as a dye. After the
initial charge of the reactants and further components, a
vacuum/nitrogen purging cycle is initiated with agitation by upward
blade rotation direction. The vacuum/nitrogen purging cycle
consists of an evacuation to pressures less than 200 mTorr followed
by the introduction of nitrogen gas. The v/n cycle is repeated once
again to ensure a dry atmosphere. At the end of the final nitrogen
purge, the pressure is adjusted to be slightly above one atmosphere
and the oil temperature controller is set to a desired reaction
temperature, preferably about 140.degree. C., while the rotational
speed of the agitator is maintained at the same rotational speed
and in an upward direction for the reminder of the run. The
reaction can proceed at the set temperature for upwards of about 6
hours, followed by 2 hours at 150.degree. C., and finished with 1
hour at 100.degree. C. before discharge. In a preferred cycle, a
total of 9 hours of polymerization is performed as outlined
above.
[0029] In another embodiment, a jacketed twin cone reactor (CV) can
be used that had intersecting dual helical-conical blades that
intermesh throughout the conical envelope of the bowl. A CV reactor
is a low speed, medium shear style rector with excellent mix
dispersement characteristics. High viscosity polymerization and
condensation reactions are routinely accomplished in helicone
mixers.
[0030] The resulting polymer melt blend is purged through an
extruder until the feed is consistent, at which point vacuum is
applied to wo vacuum ports. The polymer blend extrudate strands are
fed through a water bath and into the strand pelletizer. The
pelletizer cut the strands into appropriate sized pellets. This
process continues until the entire polymer melt blend is formed
into substantially uniform pellets.
[0031] In a preferred process, a Reduction Engineering Model 604
unit is utilized as the strand pelletizer. The molten polymer or
bimodal polymer blends are forced out of a ZSK-30 extruder by
pressure through a multi-hole die and passed through two water
baths (troughs) in a row, filled either with cold or hot water (20
to 70.degree. C.). The strands are then fed into the strand
pelletizer, which pulls the strands at a given speed based on
desired size. The strand pelletizer has several rotating blades
travelling the same speed as the puller motor. In a "good" case,
the strands remain uniform in size throughout the process, from the
die through the water troughs and into the pelletizer, generating
at the end uniform pellets.
[0032] For poly(p-dioxanone) strand-pelletization, the extruder
zone temperatures for the preferred process are set between 140 and
160.degree. C. throughout all five zones (gradual increase in
temperature towards the end zone), having rotator speeds varying
between 175 and 225 RPM, while the batch temperature is maintained
at between 165 and 175.degree. C., and torque values between 45 and
55 Nm. Water trough temperatures are maintained at 78.degree.
F.
[0033] Preferred drying equipment can be conventional vacuum tumble
drier or a conventional fluidized bed drier, each operated within
specified parameters. Undried pellets made in accordance with the
processes described above contain a high level of unreacted monomer
and are very hydroscopic (absorbing potentially high level of
moisture from the air). If the moisture in pellets is not removed
prior to the heat treatment of undried pellets in a dryer,
degradation of the material can occur. For this reason, it is
recommended to pull vacuum at room temperature on undried samples
at the start of drying cycle for about 8-12 hours.
[0034] The moisture analysis data are summarized in the table below
for undried pellets made in accordance with the inventive process.
It was found that the moisture level of the resulting pellets
increased from the time of polymer discharge (450-500 ppm) to the
moment the prepared pellets were ready to enter the dryer's cycle
(1,524 ppm, at relative humidity (RH) in the room of about
30%).
TABLE-US-00001 TABLE Moisture Data for Undried Pellets of Example 1
during the Vacuum Stage as a Function of Drying Time at Room
Temperature Vacuum Water Room RH (%) time (h) (ppm) during the run
Comments 0 1,524 31 Pellets appeared sticky after the test 20 496
32 Pellets slightly sticky 28 76 29 Non-sticky pellets 48 26 41
Non-sticky pellets
[0035] The data shows that more than 24 hours of vacuum at ambient
temperature to reduce moisture level in pellets below 100 ppm,
which is considered low enough to proceed with the next drying
cycle step. So, instead of standard 8-12 hours of vacuum time that
has been used conventionally for absorbable polymers, including
poly(p-dioxanone) ground resin, at least 28-hour vacuum cycle
should be used, preferably from 28 to 48-hour vacuum cycle for
poly(p-dioxanone) undried pellets. This modified vacuum cycle
produces pellets with less sticking, as well as reducing polymer
degradation.
[0036] Different characterization methods, described below, were
used to measure key properties of the poly(p-dioxanone) resins and
its fibers to support this application. calorimetric data were
generated on a TA Instruments' Differential Scanning calorimeter,
DSC Model 2910 MDSC, using dry Na as a purge gas. Typically, about
5-10 mg of a polymer resin or a fiber was placed in an aluminum
pan, secured by a lid (cover), and positioned in the autosampler
holder area of the instrument. Two types of non-isothermal
conditions are employed: a) First heat scan: a polymer or a fiber
was quenched to -80.degree. C., followed by the constant heating
rate at 10.degree. C./min up to 140.degree. C.; and b) Second heat
scan: after melting of a sample at 140.degree. C. for three
minutes, a polymer or a fiber was quenched below its glass
transition temperature (-80.degree. C.), followed by the controlled
heating step with the constant rate of 10.degree. C./min. The first
heat scan data are indicative of "as is" properties of a sample
and, as such, largely dependent on its thermal history. The second
heat data, on the other hand, are independent of thermal history of
the sample and are a function of the inherent properties of the
sample (chemistry, molecular weight, monomer level, etc.). From the
first heat scan data, in addition to the glass transition
temperature and melting point, the heat of fusion, .DELTA.Hm, as an
area under the melting peak and expressed typically in J/g, can be
obtained. Heat of fusion is directly proportional to the level of
crystallinity in a sample.
[0037] Morphological data were obtained by conventional Wide Angle
X-Ray Diffraction (WAXD) analysis. The WAXD measurements of a dried
resin or a fiber were carried out on a Siemens Hi-Star.TM. unit
using CuK.alpha. radiation at a wavelength of 1.542 .ANG.. The
instrument was operated at 40 kV and 40 mA with a collimator
diameter of 0.5 mm. The convolution of the X-ray images and the
calculation of crystallinity content were conducted using the
DIFFRAC PLUS.TM. software developed by Siemens.
[0038] Inherent viscosity (IV) measurements were conducted in
hexafluoroisopropanol (HFIP) at 25.degree. C. and at a
concentration of 0.10 g/dL. The molecular weight measurements were
performed using Gel Permeation Chromatography (GPC) equipped with
Wyatt's Optilab rEx refractometer and Wyatt's HELEOS II multi-angle
laser light scattering detector. During the measurements, PL HFIP
gel columns were maintained at 40.degree. C., with a mobile phase
consisting of HFIP with 0.01M LiBr (0.2% H.sub.2O) operating at the
flow rate of 0.7 ml/min. Empower and Astra software were used for
data analysis. Two PL HFIP gel columns were used operated at
40.degree. C., and HFIP with 0.01 M LiBr (0.2% H.sub.2O) as a
mobile phase. Flow rate was 0.7 mL/min with injection volume of 70
.mu.L. Solution concentration was approximately 2 mg/mL.
[0039] The Nuclear Magnetic Resonance (NMR) method identifies and
determines the chemical composition of polymer resins and fibers
using proton nuclear magnetic resonance (.sup.1HNMR) spectroscopy.
The instrument used was the 400 MHz (9.4 Tesla) Varian Unity INOVA
NMR Spectrometer; an appropriate deuterated solvent, such as
Hexafluoroacetone sesquideuterate (HFAD) of at least 99.5% purity D
(ETHICON ID #2881, CAS 10057-27-9) was used. Sample preparation: In
triplicate, 6-10 mg of each sample was weighted and placed into
separate 5 mm NMR tubes. Under nitrogen gas in a glove box,
300+/-10 .mu.L of HFAD was added using 1000 .mu.L syringe, to each
NMR tube and cap. Meanwhile, a solvent blank was prepared. The
samples were then removed from the nitrogen glove bag/box and NMR
tube(s) were placed in a sonic bath, and sonicated until the sample
was dissolved, and no evidence of solid polymer existed. Subjecting
the samples again under the nitrogen flow, 300+/-10 .mu.L
benzene-d6 was added using a 1000 .mu.L syringe to each NMR tube
and capped. The tubes were shake well to ensure uniform mixing of
the HFAD and benzene-d6 solvents.
[0040] Mechanical properties of the fibers (monofilaments) before
and after post-processing, including hydrolysis treatment, such as
straight tensile and knot tensile strength (one simple knot in the
middle) were measured by the Instron tester. The Instron model was
ID #TJ-41, equipped with 100-lb load cell LC-147 with pneumatic
grips at clamping pressure around 60 psi. For the regular tensile
measurements of non-hydrolyzed (time zero) samples, steel faces
were used on the Instron machine. The gage length was 5 inches; a
sampling rate of 20 pts/secs with a crosshead speed of 12 in/min
was employed. The full-scale load range was 100 lbf. For hydrolysis
testing (Breaking Strength Retention, BSR measurements), rubber
faces were used to avoid slippage. The fiber diameters were
measured using Federal gauge (Products Corp. Providence, R.I.)
model #57B-1, identification #W-10761.
[0041] To follow conversion of a p-dioxanone monomer in real
polymerization time, a FT-NIR spectrometer [Antaris II Fourier
Transform Near Infrared Spectrometer, supplied by ThermoFischer
Scientific] equipped with a 1/4'' diameter transmission probe and
2-meter optical cable was used. TQ Analyst Software was used to
analyze real-time NIR spectra. The overall scanning (collection)
time was set to 64 scans, with 8 cm.sup.-1 spectral resolution.
Exactly every two minutes the spectra were collected as a function
of reaction time. The area under the carbonyl peak (the first
harmonic overtone of a combination band), located at about 4,620
cm.sup.-1 was used to monitorp-dioxanone conversion. An NIR
transmission probe (supplied by Axiom) was placed in the lower part
of the vessel, at the same level/height where a thermocouple
measuring the batch temperature sits.
[0042] The water content in poly(p-dioxanone) pellets were obtained
using Computrac Vapor Pro Moisture Analyzer (Arizona Instruments
LLC, AZ). The instrument utilizes a cylinder-shaped bottle heater,
a dry air-carrier gas flow system and a moisture sensor. The
instrument heats the sample (recommended 10.degree. C. below its
glass transition temperature) contained in a 25 ml septum vial.
Volatiles driven from the sample are carried by the air system
through the Sensor Block containing a Relative Humidity (RH)
sensor. The reading from this sensor is combined with the sensor
block temperature and carrier gas flow rate in a microprocessor to
generate a measurement of the moisture content in the sample. A
typical procedure for measuring the water level in pellets follows.
After performing a dryness test and calibrating the RH sensor,
about 1 g of pellets (accurately measured by an analytical balance)
is placed into a glass septum vial. The sample in the vial is then
inserted in the instrument, which is preheated at 90.degree. C. and
the measurements of released water is begun. At the end of the run
the following parameters are displayed on the screen: the water
level in parts per million (ppm), total amount of water released in
micrograms, and exposure time in minutes. Typically, the test lasts
from about 5 to 10 minutes, depending on the sample weight: larger
samples take longer time for all the water to be released form a
sample.
[0043] The following examples are illustrative of the principles
and practice of the present invention, although not limited
thereto. Numerous additional embodiments within the scope and
spirit of the invention will become apparent to those skilled in
the art once having the benefit of this disclosure.
REFERENCE EXAMPLE
[0044] As shown below, poly(p-dioxanone) polymer prepared by
standard synthetic procedures as described in U.S. Pat. Nos.
4,052,988, 5,717,059, and 6,448,367B1 cannot be pelletized by a
strand-pelletization procedure. In addition, bimodal polymer blends
of poly(p-dioxanone) described in U.S. Pat. No. 8,236,904B2, and
U.S. Pat. No. 8,450,431B1 despite having enhanced crystallization
properties and low level of residual monomer, fail to pelletize
using a standard, strand-pelletization technique.
[0045] Due to the "soft" nature of poly(p-dioxanone) and inability
of the polymer to crystallize fast enough in the water troughs, the
resin stuck to the die, making it very difficult to maintain
uniform strand diameter, with many breaks occurring at the die.
Even when part of the strands made it to the pelletizer, the
strands were difficult to cut because of the "soft"
poly(p-dioxanone), and the resulting pellets (if any) were not of
the desired length or shape. Due to these difficulties, the process
of pelletizing poly(p-dioxanone) and bimodal polymer blends of
poly(p-dioxanone) was aborted.
Example 1. Inventive Large-Scale Synthesis Conditions of Melt
Polymerized p-Dioxanone, PDO
[0046] This example describes the synthesis of a melt polymerized
poly(p-dioxanone), and a subsequent underwater pelletization of
high monomer content resin (34 mole %) produced in the larger-scale
15-gallon Benco-style reactor. Throughout the polymerization,
monomer conversion was monitored in real-time by remote FT-NIR
spectroscopy (Antaris II, Thermo) using a 1/4'' NIR transmission
probe (supplied by Axiom).
[0047] Using a large-scale 15-gallon stainless steel Benco reactor
equipped with an oil jacket and agitation, 65,000 grams of
p-dioxanone monomer were added along with 98.87 grams of dodecanol
(DD) initiator, 43.13 ml of a 0.33M solution of stannous octoate
catalyst in toluene, and 65 grams of D&C Violet Number 2 dye
(0.1 wt. %). After the initial charge, a vacuum/nitrogen purging
cycle with agitation at a rotational speed of 10 RPM in an upward
direction for 25 minutes was initiated. The reactor was evacuated
to pressures less than 200 mTorr followed by the introduction of
nitrogen gas. The cycle was repeated once again to ensure a dry
atmosphere. At the end of the final nitrogen purge, the pressure
was adjusted to be slightly above one atmosphere and the oil
temperature controller was set to 140.degree. C., while the
rotational speed of the agitator was maintained at 10 RPM in an
upward direction for the reminder of the run. The reaction
proceeded at 140.degree. C. for 6 hours, followed by 2 hours at
150.degree. C., and finishing with 1 hour at 100.degree. C. before
discharge. A total of 9 hours of polymerization was performed.
[0048] During the polymerization at selected time intervals, a
small amount of sample was removed from the reactor, and sent to
analytical testing, including DCS, NMR, GPC, and IV measurements.
An additional information was obtained using a FT-NIR spectrometer
by following conversion of p-dioxanone, PDO monomer in real
polymerization time. Due to the thermodynamic equilibrium nature
between PDO and its polymer, the achievable monomer conversion in
these types of melt polymerization is rather low; consequently, a
discharged resin contained a lot of unreacted monomer.
[0049] The polymerization rate, as evidenced by the slope of the
line in FIG. 3, was relatively fast at the beginning of the
reaction, but slowed considerably in later stages of the reaction.
From about 300 minutes of reaction, the monomer conversion seemed
to level off at about 25 mole % monomer content. Longer reaction
time under these polymerization conditions does not seem to benefit
polymer properties.
Reference Example 2. Underwater Pelletization of
Poly(p-Dioxanone)
[0050] Poly(p-dioxanone) polymer produced by the melt reactor-only
process of Example 1 failed to produce pellets by using selected
set of pelletizing conditions, known to work previously with other
absorbable polyesters.
[0051] At the end of the final reaction period of the Example 1,
the agitator speed was reduced to 4.0 RPM in the downward
direction, and the polymer was attempted to discharge using the
Gala underwater pelletizing apparatus. The die hole size was
0.093'' with 4 holes opened. The die temperature was set at
95.degree. C., with the pump and cutter speed of 12 RPM, and 3,600
RPM, respectively. The melt temperature was 109.degree. C., and
water temperature flow kept at 40.degree. C. Except for temperature
profiles of a die and melt, these are the standard conditions used
for underwater pelletization of other absorbable polymers including
polyglycolide homopolymer and at least some lactide and glycolide
copolymers.
[0052] Using these conditions, pelletization failed because the
polymer was not able to cut, wrapping around a die fixture. The
resin appeared too soft.
Example 2. Underwater Pelletization of Poly(p-Dioxanone)
[0053] At the end of the final reaction period of the Example 1,
the agitator speed was reduced to 4 RPM in the downward direction,
and the polymer was discharged using the Gala underwater
pelletizing apparatus. The pelletizer material output was about
64.8 kgs/hr, yielding a net weight of 60.3 kg. Upon cooling,
uniform oval-shaped pellets were placed in the freezer for storage
until drying. The pellets were then placed into a 3-cubic foot
Patterson-Kelley tumble dryer to help remove residual monomer.
Compared to the failed underwater pelletization process of
Reference Example 2, several important changes were made. These are
displayed in Table 1.
TABLE-US-00002 TABLE 1 Gala Pelletizer Conditions used to Process
the Polymer of Example 2 Example Pump Set Die Cutter Melt Set Water
# of holes Die hole # RPM T (.degree. C.) RPM T (.degree. C.) T
(.degree. C.) opened size (in) Ref. 2 12 95 3,600 109 40 4 0.093
Ex. 2 6 to 13 115 3,415 126 15 2 0.093
Instead of starting the pump at a rotational speed (RPM) directly
to 12, the process was initiated with a rotation speed of 6 RPM,
and then gradually increased to 11 or 13 RPM, depending on a
desired pellet size. Also, the die temperature was set to a higher
temperature (115.degree. C.), while the water temperature was kept
at about 22.degree. C. (set at 15.degree. C., but unable to
maintain that low). The number of holes was reduced to 2, though it
is not believed that this change affects the ability of the resin
to be pelletized.
[0054] Table 2 summarized the major properties of time-series
samples as well as those of the discharged pellets of Example 2 at
the beginning, at the middle, and at the end of discharge.
TABLE-US-00003 TABLE 2 Physical Properties of Polymerized PDO Resin
of Example 1 as a Function of Reaction Time Mole % Second heat DSC
data Sample PDO Mw IV T.sub.g T.sub.c .DELTA.H.sub.c T.sub.m
.DELTA.H.sub.m ID (NMR) (g/mol) (dL/g) (.degree. C.) (.degree. C.)
(J/g) (.degree. C.) (J/g) 0 + 4 hrs 44.4 76,700 0.65 -59.4 9.9 27.7
80.6 39.9 0 + 6 hrs 37.2 80,100 0.84 -52.7 18.0 33.5 84.8 42.9 0 +
8 hrs 35.8 74,500 0.75 -48.4 22.8 33.8 86.9 43.4 0 + 9 hrs 34.7
73,200 0.83 -48.8 20.2 34.3 86.6 44.5 Start 34.5 74,400 0.82 -47.0
23.0 33.3 87.6 43.3 pellets Middle 34.1 74,000 0.84 -45.8 23.5 34.7
88.4 43.8 pellets End 33.2 73,900 0.81 -45.7 23.7 35.9 88.5 45.9
pellets
[0055] Table 2 indicates that discharged undried pellets contain
about 34 mole % of unreacted monomer based on NMR analysis. The
data highlights that there is no significant difference in physical
properties between pellets at the beginning, at the middle, and at
the end of discharge, which suggest high pellet uniformity.
Reference Example 3. Standard Drying Procedures Applied to Undried
Pellets
[0056] This example illustrates that the standard drying conditions
for poly(p-dioxanone) granular resin cannot be used to produce the
pellets of the present invention. Undried poly(p-dioxanone) pellets
produced using procedures of Example 1 (no vacuum stage used)
yielded following physical properties: weight average molecular
weight of 80,100 Daltons, an inherent viscosity of 1.33 dL/g, with
28.0 mole % of unreacted PDO monomer left. The undried pellets were
kept in a freezer for about a week prior to the drying
procedure.
[0057] The undried polymer pellets were then placed into a 3-cubic
foot Patterson-Kelley, PK tumble dryer to remove residual monomer
using a standard drying procedure applied for regular
poly(p-dioxanone) ground resin. Once charged with the undried
pellets, the Patterson-Kelley tumble dryer equipped with four
stainless steel balls was closed, a dryer rotational speed of 3 RPM
was initiated, and the pressure was reduced to less than 200 mTorr.
These conditions were maintained with no heat for 12 hours. After
the 12-hour period, the oil jacket temperature was set to
80.degree. C. and maintained for the next 48 hours while keeping
steady rotation and vacuum. However, after about 12 hours at
80.degree. C. soak, the batch had to be aborted due to a strong
sticking of pellets to each other and to the dryer's wall.
[0058] Alternative drying conditions were tried as follows: 12
hours dwell at room temperature followed by 8 hrs@45.degree. C., 8
hrs@70.degree. C., 48 hrs@80.degree. C., and finishing with 3
hrs@90.degree. C., all vacuum stages. After cooling, the polymer is
discharged from the dryer by pressurizing the vessel with nitrogen,
opening the discharge valve, and allowing the polymer granules to
descend into waiting vessels for long term storage.
[0059] It was discovered that these conditions prevented sticking
of pellets to the wall and to each other. However, although the
dried pellets contained only 1.27 mole % residual monomer, the
weight average molecular weight dropped significantly: from 80,100
Daltons to 63,500 Daltons, a decrease more than 20%. The inherent
viscosity of the resulting dried pellets increased to 1.64 dL/g,
but this is mostly due to 26% monomer removal.
Example 3. Drying Conditions of Pellets Produced in Example 1
[0060] The detailed drying procedure follows. Once charged with the
poly(p-dioxanone) pellets, the Patterson-Kelley tumble dryer was
closed, a dryer rotational speed of 4 RPM was initiated, and the
pressure was reduced to less than 200 mTorr. These conditions were
maintained with no heat for 48 hours for the undried pellets of
Example 2. After the 48-hour period, the oil jacket temperature was
set to 55.degree. C. and maintained for 2 hours, followed by
75.degree. C./2 hrs, with the final step at 95.degree. C. for 24
hours. The stepwise heating cycle during drying was found critical
to prevent sticking of the pellets as described in the Reference
Example 3. At the end of the final heating period, the batch was
allowed to cool for a period of 2 hours while maintaining steady
rotation and vacuum. After cooling, the polymer was discharged from
the dryer by pressurizing the vessel with nitrogen, opening the
discharge valve, and allowing the polymer pellets to descend into
waiting vessels for a long-term storage.
[0061] The dried pellets of Example 1 exhibited an IV of 1.54 dL/g
and a Mw of 58,600 Daltons. NMR analysis confirmed that the dried
pellets contained only 0.44 mole % of residual monomer. Wide Angle
X-Ray Diffraction (WAXD) data on the dried sample revealed 50.2%
crystallinity.
[0062] Similarly, another set of undried pellets were produced
following the polymerization procedure of Example 1, yielding a
monomer content of as high as 29 mole %. The weight average
molecular weight was 74,100 Daltons, and inherent viscosity 1.44
dL/g. The undried pellets were then subjected to the drying
procedure: 32 hours vacuum stage at room temperature, followed by 4
hrs@55.degree. C., 4 hrs@75.degree. C., with the final step of 24
hrs@95.degree. C. Again, the pellets did not experience any
sticking issues during any stage of drying. The final properties of
the dried pellets also did not show any significant decrease of the
molecular weight: calculated IV was 1.82 dL/g and a Mw was 74,800
Daltons. NMR analysis confirmed that the dried pellets contained
only 0.73 mole % of residual monomer. Wide Angle X-Ray Diffraction
(WAXD) data on the dried sample revealed 50.7% crystallinity.
Example 4. Large-Scale Synthesis Conditions of Melt Polymerized
p-Dioxanone
[0063] Using a 10-gallon stainless steel oil jacketed CV reactor
equipped with corotating agitation, 30,000 grams of PDO monomer was
added along with 44.51 ml of monofunctional initiator (dodecanol,
DD) and 19.91 ml of a 0.33M solution of stannous octoate in
toluene. The dye, D&C Violet Number 2 (24 grams, 0.08 wt. %),
was added as well. After the initial charge, a vacuum/nitrogen
purging cycle with agitation at a rotational speed of 7.5 RPM in an
upward direction was initiated. The reactor was evacuated to a
pressure of less than 350 mTorr followed by the introduction of
nitrogen gas. The cycle was repeated once again to ensure a dry
atmosphere.
[0064] At the end of the final nitrogen purge, the pressure was
adjusted to be slightly above one atmosphere. The rotational speed
of the agitator was kept at 7.5 RPM in an upward direction. The
vessel was heated by setting the oil controller at 120.degree. C.
When the batch temperature reached 100.degree. C., rotation of the
agitator was switched to a downward direction. The reaction
continued for 4.0 hours from the time the batch temperature reached
100.degree. C. After four hours at 120.degree. C., the reactor
temperature was reduced to 100.degree. C., and kept at that
temperature for additional 4.0 hours before vacuum stage. The
vacuum stage lasted two hours, followed by the discharge via
underwater pelletization. Throughout the polymerization, monomer
conversion was monitored in real-time by remote FT-NIR spectroscopy
(Antaris II, Thermo) using a 1/4'' NIR transmission probe (supplied
by Axiom).
[0065] As in the previous inventive Example 2, at the end of the
final reaction period, the agitator speed was reduced to 4 RPM in
the downward direction, and the polymer was discharged using the
Gala underwater pelletizing apparatus. The die hole size was
0.093'' with 2 holes opened. The die temperature was kept between
110 and 130.degree. C., with the pump and cutter speed of 14 RPM,
and 3500 RPM, respectively. The pelletizer material output was
about 51.0 kgs/hr, yielding a net weight of 19.7 kg. During the
2-hour vacuum stage, about 5.7 kg of PDO monomer was removed. Upon
cooling, uniform oval-shaped pellets were placed in the freezer for
storage until drying. The pellets were then placed into a 3-cubic
foot Patterson-Kelley tumble dryer to help remove residual
monomer.
[0066] Until up to the vacuum stage, the reaction kinetics of this
run is comparable to the previous Example 2, leveling off at about
25 mole %. However, after the introduction of the 2-hour vacuum
step, the monomer level dropped significantly and surprisingly to
about 10% content. Potential advantages of having poly(p-dioxanone)
pellets with less monomer content prior to the drying stage are:
potentially less moisture uptake, and thus, less polymer
degradation, higher storage stability of undried pellets, less
footprint (smaller cold trap needed), and faster drying procedure.
Table 3 summarized the major properties of time-series samples as
well as those of the discharged pellets at the beginning, at the
middle, and at the end of discharge.
TABLE-US-00004 TABLE 3 Physical Properties of Polymerized PDO resin
of Example 4 as a Function of Reaction Time, including Discharged
Undried and Dried Pellets Mole % Second heat DSC data Sample PDO Mw
IV T.sub.g T.sub.c .DELTA.H.sub.c T.sub.m .DELTA.H.sub.m ID (NMR)
(g/mol) (dL/g) (.degree. C.) (.degree. C.) (J/g) (.degree. C.)
(J/g) 0 + 4 hrs 50.8 82,100 0.96 -63.6 5.6 24.0 78.8 34.2 0 + 8 hrs
31.1 83,900 1.39 -42.9 21.6 34.5 89.9 41.7 0 + 9 hrs 22.3 83,200
1.52 -34.0 29.8 39.6 94.3 46.1 V + 1 0 + 10 hrs 15.1 80,000 1.67
-27.1 36.3 42.8 97.8 48.2 V + 2 Start 16.4 80,200 1.63 -25.0 37.1
42.2 98.7 47.2 pellets Middle 16.2 80,200 1.63 -26.3 35.5 42.3 97.9
48.2 pellets End 16.8 80,900 1.63 -26.8 36.8 41.1 97.7 47.3 pellets
Dried 2.03 80,500 1.95 -11.7 47.9 48.5 105.5 50.9 pellets
[0067] Table 3 indicates that the resin prior to discharge
contained 15.1% residual monomer based on NMR analysis (16.1% based
on real-time NIR data), and undried pellets contained on average
16.5% of unreacted monomer. No difference in physical properties
between pellets at the beginning, at the middle, and at the end of
discharge indicates high pellet uniformity. The pellets were dried
using the conditions from Example 3, contained 2 mole % residual
monomer with weight average molecular weight (GPC) of 80,500 g/mol,
and inherent viscosity of 1.95 dL/g.
[0068] With reaction progress and subsequent monomer removal,
calorimetric properties, as measured by the second heat runs, are
strongly affected, as indicated in Table 3. The glass transition
temperature increased gradually, as the population of polymer
chains increases in the system. Crystallization temperature and
crystallinity level rise, as well as melting point and heat of
fusion as monomer is being converted into the polymer.
Example 5. Large-Scale Synthesis Conditions of Melt Polymerized
p-Dioxanone, PDO Using Reduced Catalyst Concentration
[0069] During standard, solid state (oven curing) treatment, a
higher catalyst concentration is needed to advance the reaction
(initiation and chain propagation) due to diffusion difficulties in
the solid, crystallized matrix. A lower catalyst concentration can
improve resin chemical stability during various processing, such as
extrusion, injection molding, sterilization, suture barbing,
etc.
[0070] Polymerization was carried out in a small 2-gallon reactor
having no pelletization capability. Using a 2-gallon stainless
steel oil jacketed CV reactor equipped with corotating agitation,
7,000 grams of PDO monomer was added along with 12.98 ml of
monofunctional initiator (dodecanol, DD) and 2.6 ml of a 0.33M
solution of stannous octoate in toluene. The dye, D&C Violet
Number 2 (7 grams, 0.1 wt. %), was added as well. After the initial
charge, a vacuum/nitrogen purging cycle with agitation at a
rotational speed of 7.5 RPM in an upward direction was initiated.
The reactor was evacuated to pressures less than 80 mTorr followed
by the introduction of nitrogen gas. The cycle was repeated once
again to ensure a dry atmosphere. At the end of the final nitrogen
purge, the pressure was adjusted to be slightly above one
atmosphere. The rotational speed of the agitator was kept at 7.5
RPM in an upward direction. The vessel was heated by setting the
oil controller at 140.degree. C. When the batch temperature reached
100.degree. C., rotation of the agitator was switched to a downward
direction. The reaction continued for 6.0 hours from the time the
batch temperature reached 100.degree. C. After six hours at
140.degree. C., the reactor temperature was reduced to 100.degree.
C., and kept at that temperature for additional 3.0 hours including
the last 2-hours under the vacuum. The resin was discharged into
aluminum packs, and kept in the freezer prior to grinding and
sieving operations. The drying procedure was conducted according to
the methods described in the Example 3.
[0071] Reaction kinetics was found only slightly slower compared to
those of Examples 1 and 4 presented earlier, despite almost only a
half catalyst used (monomer: catalyst=80,000:1 vs. 44,700:1 used in
Ex. 1 & 4). The resin prior to discharge contained about 21
mole % residual monomer based on NMR analysis, or 19 mole %
calculated by FT-NIR method.
[0072] The dried pellets of this example exhibited an IV of 1.96
dL/g and a Mw of 84,100 Daltons. NMR analysis revealed that the
resin contained 0.58 mole percent of unreacted monomer. Wide Angle
X-Ray Diffraction (WAXD) data on the dried sample revealed 49.3%
crystallinity.
Example 6. Large-Scale Synthesis Conditions of Melt Polymerized
p-Dioxanone
[0073] The resin for this example was produced in the same manner
as described in Example 4, except that slightly modified
temperature profile is used. After charging the monomer, catalyst,
initiator, and a dye, the reactor temperature was set to
120.degree. C., and kept at that temperature for full 8.0 hours,
followed by 2-hour vacuum stage at 100.degree. C. The underwater
pelletization was conducted at the same manner as in Example 4,
yielding about 18.1 kg of nice pellets. The drying was conducted
using conditions of Example 3.
[0074] The dried pellets of this example exhibited an IV of 2.10
dL/g and a Mw of 90,100 Daltons. NMR analysis revealed that the
resin contained 0.67 mole percent of unreacted monomer. Wide Angle
X-Ray Diffraction (WAXD) data on the dried sample revealed 53%
crystallinity.
Example 7. Post-Processing of the Inventive Large-Scale Synthesis
Conditions of Melt Polymerized p-Dioxanone
[0075] The dried pellets of Example 6 were used to produce
monofilaments of two USP suture sizes: 2-0 and Size 0. The
monofilament procedure details follow. The pellets of Example 6
were extruded using a single-screw Jenkins one inch extruder with a
24:1 barrel length, having 1-22-1 screw design, and equipped with a
single grooved feed throat. The die had a diameter of 70 mils; the
die temperature was set for both sizes at 115.degree. C. After
passing through an air gap of 0.375 inch, an extrudate was quenched
in a 22.degree. C. water bath.
[0076] After exiting the water bath, the fibers entered an air
quench cabinet that was utilized to increase the crystallization
level of the undrawn fiber before orientation. An appearance of a
well-defined and stable draw point is an insurance that the fiber
generated enough crystallinity prior to orientation/stretching. An
air quench cabinet was heated at 85.degree. F. with monofilaments
underwent either one passage (wrap) or multiple wraps. The
difference is in total residence time that non-oriented fibers
spent in a cabinet. For instance, to complete a one passage through
air cabinet requires 135 seconds, while four wraps require 590
seconds. However, it was observed that the polymer produced in
Example 6 crystallize relatively fast, and that there was
practically no difference in the final fiber physical properties
when subjected to these two residence time conditions. The fiber
line was then directed toward a first set of unheated godet rolls
at a linear speed of 10 fpm. Between first and second sets of
godets an infra-red oven was placed preheated at 128.degree. C. to
allow easier and more uniform draw. The monofilaments were then
directed toward a second set of unheated godet rolls operating at
54 fpm. The fiber line was then directed through a 6-foot hot air
oven at 97.degree. C. to a third set of unheated godet rolls; this
set of rolls was operating at 58 fpm. The line was then directed
through a second 6-foot hot air oven at 107.degree. C. to a fourth
set of unheated godet rolls. This last set of rolls was operating
at 44.1 fpm, which is a lower speed than the previous set of godet
rollers allowing the fiber to relax for better handling
characteristics (24%). The overall draw ratio was 4.41 for size
2-0, and 4.56 for size 0 monofilaments.
[0077] These monofilament extrusions went smoothly with no breaks,
with very stable draw points, which largely contributed to a
uniform fiber diameter, and reliable tensile properties. Prior to
sterilization, the fibers were annealed at 85.degree. C. for six
hours on straight rack (0% rack relaxation). Selected annealed
fiber samples were then subjected to suture packaging steps using
relay trays with Monadnock drying paper and 8-ups foil types. These
samples were then sent for ethylene oxide (EO) sterilization using
nominal "X" cycle. To remove residual EO particles following the EO
sterilization, the samples were placed in a hot room preheated at
50.degree. C. for three days.
[0078] Tensile properties of unannealed, annealed, and annealed and
sterile poly(p-dioxanone) monofilaments produced by the methods of
the present invention were evaluated next. They were determined
using an Instron testing machine using the procedures described
earlier in the text. Selected tensile properties (mean values) are
listed In Table 4. Knot tensile measurements were made with a
single knot made in the middle of the thread.
TABLE-US-00005 TABLE 4 Tensile Properties of Unannealed, Annealed,
and Annealed and Sterile 2-0 and size 0 Poly(p-dioxanone)
Monofilaments Final Straight Knot Young's Example Diameter
Annealing Draw Tensile Elong. Tensile Modulus ID (Mils) Conditions
Ratio (Lbs) (%) (Lbs) (Kpsi) Ex. 7 2-0 14.32 None 4.41x 11.89 51.2
7.24 116 Ex. 7 2-0-A 14.04 85.degree. C./6 hrs 4.41x 11.54 50.2
7.45 185 Ex. 7 2-0-AS 14.09 85.degree. C./6 hrs + 4.41x 11.65 51.3
7.37 212 EO sterile Ex. 7 Size 0 18.14 None 4.56x 18.59 50.1 10.9
128 Ex. 7 Size 0-A 17.91 85.degree. C./6 hrs 4.56x 17.93 50.6 10.9
176 Ex. 7 Size 0-AS 18.03 85.degree. C./6 hrs + 4.56x 18.23 53.1
12.0 205 EO sterile
[0079] As data from Table 4 indicates, outstanding tensile
properties were obtained for poly(p-dioxanone) monofilaments made
from the inventive processing steps. After annealing and
sterilization steps, most of the properties remain intact, except
for the Young's Modulus, which increased. Annealing and EO
sterilization due to higher crystallinity level achieved in these
samples. Higher crystallinity level (confirmed by WAXD and
calorimetric measurements) seems to have slight positive effect on
knot strength, but none on the straight tensile strength.
* * * * *