Pharmaceutical Research, Vol. 10, No.4, 1993
`
`Report
`
`The Influence of Thermal Treatment
`on the Physical-Mechanical and
`Dissolution Properties of Tablets
`Containing Poly(oL-Lactic Acid)
`
`Marcelo 0. Omelczuk1' 3 and James W. McGinity2
`
`0
`
`0
`
`Received March 5, 1992; accepted October 20, 1992
`Five molecular weight grades of poly(DL-lactic acid) (PLA) were
`incorporated as organic and aqueous pseudolatex binders into ma-
`trix tablet formulations containing microcrystalline cellulose and the
`model drug theophylline. The tablets were thermally treated to tem-
`peratures above and below the glass transition temperature (T J of
`the PLA. The results of the dissolution studies showed that ther-
`mally treating the tablets to temperatures above the T of the PLA
`g
`significantly retarded the matrix drug release compared to tablets
`which were not thermally treated. The retardation in drug release
`could be attributed to a stronger compact and a more efficient re-
`distribution of polymer throughout the tablet matrix, based on fun-
`damental principles of annealing. In addition, results from tablet
`index testing supported the dissolution results. The bonding index of
`the compact formulations increased after thermal treatment above
`the T8 of the PLA. Gel permeation chromatography and differential
`scanning calorimetry studies demonstrated that thermal treatment
`had no significant effect on the molecular weight and the glass tran-
`sition temperature of (PLA) alone and in combination with other
`components of the tablet formulation.
`KEY WORDS: poly(DL-lactic acid); cellulose; pseudolatex; tablets;
`thermal treatment; theophylline tablets.
`
`INTRODUCTION
`Thermal treatment or annealing of polymers refers to a
`process by which a polymer is heated to a certain tempera-
`ture, for a specified time period. Annealing of amorphous
`polymers usually requires the heating of the polymer to tem-
`peratures above the Tg, where the stress relaxation and ori-
`entation are the most rapid. After annealing at these high
`temperatures, the polymer sample is cooled gradually to
`avoid introduction of unwanted stresses or defects. This
`type of treatment often influences the mechanical properties
`of polymers and is associated with the time-dependent na-
`ture of the glass transition. In general, annealing increases
`the density within the polymer compared to quenching pro-
`cesses and decreases the rate of creep or stress relaxation at
`temperatures below the Tg. These changes tend to improve
`the dimensional stability of the polymer, as well as remove
`any residual stresses, strains, or defects that may have oc-
`curred during processing. Annealing generally produces
`polymers which display higher moduli and tend to be more
`
`1 Sandoz Research Institute, Sandoz Pharmaceuticals, East Han-
`over, New Jersey 07936.
`2 Drug Dynamics Institute, College of Pharmacy, The University of
`Texas at Austin, Austin, Texas 78712.
`3 To whom correspondence should be addressed.
`
`brittle than unannealed polymers (1,2). In reference to the
`annealing processes just described, the therinal treatment of
`polymeric pharmaceutical dosage forms has been studied in
`only a few cases. Curing processes can significantly affect
`the drug release rate from beads or tablets coated with aque-
`ous polymeric coatings (3-7). In these cases, the curing pro-
`cess can be defined as the heating of the coated product for
`a specified time period at the end of the coating process. The
`authors concluded that curing at temperatures above the Tg
`of the film could significantly improve film formation by en-
`suring full coalescence of the latex nanoparticles, as well as
`repairing any strains or defects. This in tum, could reduce
`the permeability of the film and avoid accelerated and irre-
`producible dissolution results. In addition, Ghali and co-
`workers (8) reported on the thermal treatment of pellets con-
`taining waxes as matrix retardants. The authors found that
`heating to temperatures above the melting point of the wax
`reduced the disintegration of some of the pellet formulations
`and resulted in a sustained drug release.
`In a recent study, we reported on the influence of mo-
`lecular weight and related properties on the drug release of
`matrix tablets utilizing PLA as a binder and retardant poly-
`mer (9). In the present investigation, the primary objective
`was to study the influence of thermal treatment on the phys-
`ical-mechanical and dissolution properties of theophylline
`tablet formulations containing PLA.
`
`MATERIALS
`
`The five molecular weight grades of poly(DL-lactic acid)
`(PLA) and other materials used in this study were supplied
`by various manufacturers: 3500 Mw PLA and microcrystal-
`line cellulose (Avicel PHlOl), FMC (Princeton, NJ); 42,000
`and 138,000 Mw PLA, Birmingham Polymers (Birmingham,
`AL); 92,000 Mw PLA, Boehringer lngelheim (lngelheim,
`Germany); 553,000 Mw PLA, Dupont (Wilmington, DE); and
`theophylline anhydrous, Sigma Chemical (St. Louis, MO).
`
`METHODS
`
`Tablet Fomtulation/Dissolution
`
`The model drug theophylline (25%) was mixed with the
`excipient (60%) in a twin shell blender. The PLA (15%) was
`incorporated into the tablet formulation as a binder by dis-
`solving the polymer in methylene chloride to a concentration
`of 20-30%. A wet granulation process was used to distribute
`the polymer solution into the powder blend using a conven-
`tional bowl mixer. The granulations were then air-dried
`overnight at room temperature and sieved through a 20-mesh
`screen. Tablets weighing 300 mg were manually compressed
`using a Carver 25-ton laboratory press with sufficient force
`to achieve a solid fraction of 0.72. True density measure-
`ments were determined using a helium pycnometer (Mi-
`cromeritics Corp., Norcross, GA). The solid fraction or po-
`rosity was kept constant in order to minimize unwanted vari-
`ables when comparing drug release and compaction
`properties.
`
`0724-8741/93/0400·0542$07.00/0 © 1993 Plenum Publishing Corporation
`
`542
`
`KASHIV1050
`IPR of Patent No. 9,492,392
`
`

`

`Physical-Mechanical and Dissolution Properties of Poly(DL-Lactic Acid)
`
`543
`
`Matrix tablets were also prepared using aqueous
`pseudolatex dispersions of PLA. The pseudolatex was pre-
`pared using a process which colloidally dispersed the solid
`spheres of PLA in water and included a surfactant for sta-
`bilization (9-12). The procedure for manufacturing matrix
`tablets using aqueous dispersions was similar to that using
`organic solutions of PLA, except for one additional drying
`step. After air-drying overnight, part of the granulation was
`heated for 1-2 hr at 60°C. This was done as a curing step to
`ensure that the polymer within the granulation was fully co-
`alesced without excess water.
`A portion of the tablets from all formulations were ther-
`mally treated in a conventional oven at 60°C for 24 hr. For
`one formulation, tablets were also heated to 40 and 80°C.
`After heating, the tablets were allowed to cool down gradu-
`ally overnight. Dissolution studies were then performed in
`900 mL of water at 37°C using the USP XXII Apparatus 2 at
`50 rpm. Samples were analyzed by UV spectroscopy (Beck-
`man) at 270 nm for theophylline. The average dissolution
`results of three tablets were taken for each granulation. The
`coefficient of variation was less than ±5% for all results
`reported (9).
`
`Tableting Indices
`
`The same granulations used to make tablets were used
`to compress compacts for index testing. Compacts weighing
`3 g were compressed to a solid fraction of0.72 using a Carver
`press. As with the tablets, a portion of compacts from all
`formulations was also thermally treated to 60°C for 24 hr and
`allowed to cool down gradually overnight before indice test-
`ing.
`
`Tensile strength testing was achieved using an Instron
`equipped with a 1-kN load cell. Both sets of compacts, with
`and without a stress concentrator, were transversely com-
`pressed between two platens until a tensile fracture was ob-
`served. The speed of the platens was adjusted to maintain a
`time constant of 10 sec between the maximum force and lie
`times that force. The dynamic indentation hardness (P) was
`determined using a pendulum impact apparatus. The values
`of the inbound velocity, rebound velocity, and chordal ra-
`dius were used to calculate the indentation hardness. The
`indentation hardness serves as an indicator of the shear
`strength of the compact under a compressive load.
`The brittle fracture index (BFI) is defined as BFI =
`[T.fTso -1]/2, where T. is the tensile strength without a
`stress concentrator and T80 is the tensile strength with a
`stress concentrator. It indicates the ability or inability of a
`compact to relieve stresses caused by plastic deformation. A
`BFI value of 0 indicates no brittle behavior, while a BFI of
`1 indicates very high brittleness.
`The bonding index (BI) is defined as T.fP and is the ratio
`of the tensile strength (T.) of the compact after decompres-
`sion to the shear strength (P) under a compressive load. It
`indicates the fraction of strength that survives decompres-
`sion. It assumes that bonding depends on the true areas of
`contact formed between particles and that the success of this
`bonding depends on the areas of true contact that survive
`decompression, as well as the processes that influence the
`strength of these contact areas during separation (9,10,13-
`18).
`
`Molecular Weight Characterization by Gel
`Permeation Chromatography
`
`The weight-average molecular weight (Mw) was deter-
`mined using a Waters GPC system with Ultrastyragel col-
`umns. Conditions of operation were as follows: solvent, tet-
`rahydrofuran; injection volume, 20 tJ.L; column temperature,
`31°C; refractometer temperature, 32°C; flow rate, 1 mL/min;
`and solute concentration, 0.25% (w/v). The GPC system was
`calibrated using polystyrene standards in tetrahydrofuran.
`This allowed the computation of samples of unknown Mw by
`correlation of the retention time or elution volume with a M w
`distribution curve (9,20-22). An average of three determina-
`tions was made for each polymer sample.
`In order to study the effect of thermal treatment and
`possible degradation of Mw, virgin polymer samples were
`placed in small vials and heated for 24 hr at 60°C using a
`conventional oven. After thermal treatment, the polymer
`samples were allowed to cool to room temperature, followed
`by sample preparation and Mw determination as described
`above. Molecular weight determinations from these ther-
`mally treated samples were then compared to those from the
`nonthermally treated samples. In other degradation studies,
`10 300-mg tablets containing 15% (75 mg) of the same grade
`of PLA were also heated at 60°C for 24 hr. After cooling to
`room temperature, the tablets were comminuted to smaller
`particle sizes using a ceramic mortar and pestle. A 167-mg
`sample of the powder mixture (25 mg PLA) was placed in a
`vial and brought to volume with 10 mL of tetrahydrofuran.
`These vials were then sealed and rotated using a Vander-
`Camp rotator for 2 hr. The vials were then centrifuged, fol-
`lowed by filtering of the supernatant into scintillation vials
`using a glass syringe. This extraction procedure allowed the
`indirect measurement of the polymer Mw in the tablet and
`was repeated with nonthermally treated tablets in order to
`study the effect of thermal treatment on Mw.
`
`Determination of the Glass Transition Temperature Using
`Differential Scanning Calorimetry
`
`The glass transition temperatures of PLA were deter-
`mined using a Perkin Elmer DSC-2C system (Norwalk, CT).
`Six-milligram samples were heated from 265 to 360 K at
`20°C/min and then quenched to 265 K. They were then re-
`heated at the same conditions. The Tg determinations were
`calculated by extrapolating the linear portion of the thermo-
`grams above and below the glass transition and then deter-
`mining the midpoint. An average of three determinations
`was made for each polymer sample (9,23,24).
`In order to study the influence of thermal treatment,
`pure polymer samples were placed in a vial and heated to
`60°C for 24 hr using a conventional oven. They were then
`allowed to cool to room temperature overnight and tested
`the next day. The Tg values of the PLA samples were also
`evaluated by testing powder samples of tablets containing
`PLA for both thermally and non-thermally treated tablets.
`For this case, 15-mg powder samples were weighed and
`crimped into aluminum pans after comminuting several tab-
`lets using a mortar and pestle. These samples were then
`tested using the same conditions as described for the pure
`polymer samples.
`
`KASHIV1050
`IPR of Patent No. 9,492,392
`
`

`

`544
`
`RESULTS AND DISCUSSION
`The data in Fig. 1 show the dissolution profiles of tablets
`which were thermally treated at different temperatures. The
`three heating temperatures were chosen relative to the Tg of
`the pure PLA of 92,000 Mw, which was approximately 53oC.
`Thermal treatment at 40oc represented heating temperatures
`below the Tg of the PLA, while thermal treatment at 60 and
`80°C represented heating temperatures above the poly-
`mer Tg.
`Tablets which were pretreated at 40oC showed a small
`reduction in the drug release as compared to non-thermally
`treated tablets. However, tablets treated to 60 and sooc
`showed much larger reductions in the release of theophyl-
`line. The results of this study demonstrated that the effects
`of thermal treatment were related to the glass transition tem-
`peratures of the PLA. Heating the tablets to temperatures
`above the Tg significantly reduced the rate of drug release
`compared to tablets which were non-thermally treated, as
`well as tablets which were heated to temperatures below the
`the T . Physical observation of these tablets during dissolu-
`tion :tso demonstrated swelling patterns which supported
`the differences in drug release. Tablets that were heated to
`60 and 80°C exhibited almost no swelling or defects on the
`matrix surface compared to the other tablets. These results
`could be attributed to the thermomechanical behavior asso-
`ciated with the Tg. Heating the tablets to temperatures above
`the T of the polymer promoted polymer chain movement,
`which resulted in a better redistribution of polymer through-
`out the matrix after cooling. The enhanced distribution
`strengthened the tablet matrix and resulted in a tablet matrix
`of higher tortuosity and a lower porosity after swelling.
`Overall, this process resulted in a reduction in the diffusion
`and the rate of drug released.
`Tablets containing the remaining Mw grades of PLA
`were also subjected to thermal treatment at 60oC for 24 hr.
`
`100
`
`80
`
`60
`
`40
`
`20
`
`"0
`Gl
`Ill as
`Gl
`;!
`Gl ·= >.
`.c g.
`Gl .c
`1-
`
`--..-- no thermal treatment
`
`4o•c. 24hr thermal treatment
`
`60°C, 24hr thermal treatment
`
`80°C, 24hr thermal treatment
`
`o4-~-r~-.~~.-~.-~-.~-.-
`4.0
`2.0
`8.0
`10.0
`12.0
`6.0
`o.o
`
`(hr)
`Time
`Fig. 1. Influence of thermal treatment temperature on the drug re-
`lease from tablets containing 15% PLA (92,000 Mw).
`
`Omelczuk and McGinity
`
`Dissolution studies were performed and the results are
`shown in Fig. 2. With the exception of tablets containing the
`3500 Mw PLA, thermal treatment had a significant impact on
`retarding the drug release for each granulation. As seen by
`the profiles using the Higuchi relationship (25), thermal
`treatment reduced the rate constant (K) by approximately
`20% for each formulation as compared to non-thermally
`treated tablets. The thermally treated tablets also demon-
`strated much less swelling than the nontreated tablets. In
`contrast, thermal treatment had no influence on retarding the
`drug release for tablets containing the 3500 Mw PLA. Both
`the thermally and the non-thermally treated tablets disinte-
`grated very quickly, resulting in a rapid drug release. It is
`important to note that the Tg of the 3500 Mw PLA was below
`the 37°C dissolution temperature. At that temperature, the
`modulus of the PLA and the associated strength of the poly-
`mer matrix were dramatically lowered regardless of whether
`the tablets were thermally treated or not (9). In addition, it is
`important to note that the thermally treated tablets which did
`not contain any PLA also disintegrated and released theoph-
`ylline very quickly. This result ruled out any potential re-
`tardant effects which could have been brought about by in-
`teractions between the other nonpolymeric components of
`the tablet matrix (10).
`Tablet index testing was performed on thermally treated
`compacts in order to investigate the effect of thermal treat-
`ment on the compaction properties of the matrix tablet for-
`
`80
`
`Ci
`.§..
`'0 60
`
`a:
`
`40
`
`"' .. .. "' a;
`"' ·= >. J: c. 20
`0 "' J:
`
`1-
`
`0
`
`0
`
`80
`
`Ci
`.§.
`-g 60
`
`.. "' "' a;
`
`40
`
`a:
`"' ~
`>. J:
`g- 20
`"' J:
`
`1-
`
`no
`
`thermal
`
`treatment
`
`M = K ..Jt
`
`42,000 Mw
`92,000 Mw
`138,000Mw
`553,000Mw
`
`•
`
`y = 3.592 + 21.08x
`y = 1.284 + 17.27x
`y = 1.737 + 15.89x
`y. 1.575 + 15.54x
`
`R•2 = 0.99
`R•2 = 0.99
`R"2 = 0.99
`R•2 = 0.99
`
`2
`3
`Square Root of Time (..J hr )
`
`4
`
`60°C, 24 hr
`
`thermal
`
`treatment
`
`42,000 Mw
`92,000Mw
`138.000Mw
`553,000 Mw
`
`y = 0.266 + 16.94x
`y = 0.828 + 13.67x
`y = 0.509 + 12.57x
`y = 0.879 + 11.97x
`
`R•2 = 0.99
`R•2 = 0.99
`R•2 = 0.99
`R•2 = 0.99
`
`0
`
`3
`2
`Square Root of Time ( ..Jhr )
`Fig. 2. Effect of thermal treatment and polymer ~~lecular weight
`on the matrix drug release from tablets contairung PLA.
`
`4
`
`KASHIV1050
`IPR of Patent No. 9,492,392
`
`

`

`Physical-Mechanical and Dissolution Properties of Poly(oL-Lactic Acid)
`
`545
`
`mulations. The results of bonding index testing for both the
`thermally and the non-thermally treated compacts contain-
`ing PLA are shown in Table I. With the exception of com-
`pacts containing the lowest Mw grade ofPLA, thermal treat-
`ment significantly increased the bonding index of the com-
`pact formulations containing PLA. The compaction results
`demonstrated a very good correlation with the dissolution
`proftles of the thermally treated tablets. Thermal treatment,
`above the T8 of the polymer, resulted in a better distribution
`of polymer throughout the tablet matrix. After cooling, the
`enhanced distribution manifested itself in increasing the ar-
`eas of true contact between the particles of the matrix. This
`resulted in stronger bonding and a relative reduction in the
`rate of drug released.
`The results of BPI testing for both thermally and non-
`thermally treated compacts are shown in Table I. Although
`there appears to be no correlation with Mw, the data indicate
`that the propensity for brittle behavior generally increased
`slightly after thermal treatment. However, it is important to
`note that the brittle fracture index results, on a scale of 0 to
`1, were actually very low and indicated an exceedingly small
`propensity for brittle behavior. Thus, thermal treatment of
`tablets should not pose any potential problems during pro-
`cessing which may result from minor increases in their brittle
`propensity.
`The compaction properties of tablet formulations con-
`taining PLA, as a result of thermal treatment, are also sup-
`ported by the general effects of annealing on pure polymeric
`components. As discussed in the Introduction, annealing of
`polymers often influences the mechanical properties of poly-
`mers. In general, annealing decreases the density within the
`polymer and improves the dimensional stability by raising
`the modulus (1,2). Slow cooling of annealed polymer also
`tends to remove any residual stresses, strains, or defects that
`occurred during processing. Thus, in addition to improving
`the distribution of polymer and bonding strength within the
`tablet matrix, thermal treatment may also have contributed
`to improving the bonding strength by increasing the polymer
`modulus, as well as removing any defects which could have
`disturbed the structural integrity of the polymeric network
`throughout the matrix.
`Although thermal treatment improved the bonding ca-
`pacity within the tablet matrix and retarded the rate of drug
`release, Mw degradation studies were performed in order to
`
`Table I. Influence of Thermal Treatment and Molecular Weight on
`the Bonding Index and Brittle Fracture Index of Compacts Contain-
`ing Poly (DL-Lactic Acid)
`
`Bonding index
`(X 102)
`
`Brittle fracture
`index
`
`PLA (Mw)
`
`3,500
`42,000
`92,000
`138,000
`553,000
`
`RTa
`
`1.85
`2.18
`2.69
`2.87
`2.72
`
`6oocb
`
`1.05
`2.95
`3.37
`3.55
`3.25
`
`a No thermal treatment.
`b 60°C/24-hr thermal treatment.
`
`RTa
`
`0.05
`0.08
`0.06
`0.06
`0.06
`
`60ocb
`
`0.01
`0.14
`O.o7
`0.08
`0.17
`
`ensure that thermal treatment of the tablet was not degrading
`the polymer. Gel permeation chromatography studies were
`conducted on polymer samples that were thermally treated
`to 60°C for 24 hr, using the same conditions as those used for
`thermal treatment of tablets. Figure 3 shows that there was
`a small reduction in Mw after thermal treatment for each Mw
`grade of PLA. The small reduction in polymer Mw for each
`PLA sample can be considered to have a minor influence on
`the mechanical properties of the polymer (9). The relative
`moduli of the PLA samples are not significantly sensitive to
`the Mw at temperatures well below their glass transition tem-
`peratures. In addition, the thermal stability of PLA is also
`supported by degradation studies conducted by Gupta and
`Deshmukh. (26).
`Degradation studies were also conducted on the 3500
`and 92,000 Mw samples of PLA by extracting the polymer
`from the thermally and non-thermally treated tablets. As il-
`lustrated by the bar graphs in Fig. 4, the extracted PLA
`sample experienced very small Mw reductions after thermal
`treatment, which were of the same magnitude as that dis-
`played by the pure PLA samples. The results of these deg-
`radation studies indicated that processing and manufacturing
`conditions, as well as the addition of drug and excipient, had
`no significant effect on lowering the Mw of the PLA. In
`addition, the results also ruled out the possibility of any
`excess degradation that could have been caused by thermal
`treatment and associated interactions between the compo-
`nents of the tablet formulation. Furthermore, these results
`coincide with the dissolution and compaction data, which
`demonstrate behavior that is contrary to that which would be
`expected if there was significant polymer degradation during
`thermal treatment.
`Differential scanning calorimetry (DSC) was conducted
`on pure PLA samples after thermal treatment in order to
`investigate possible changes in the T8 that may have oc-
`curred. As shown by the transition curves in Fig. 5 for the
`3500 and 138,000 Mw PLA samples, the T8 of the polymer
`samples did not demonstrate any significant changes after
`thermal treatment. In addition to pure polymer, particulates
`
`150000
`
`• Mw, no thermal treatment
`0 Mw, 60°C/24 hr thermal treatment
`
`.!!
`~ 100000
`
`::!!
`cD
`
`.. 0
`til .. Gi >
`
`c(
`
`50000
`
`3500
`
`42000
`
`92000
`
`138000
`
`PLA Mw Grade
`Fig. 3. Effect of thermal treatment on the molecular weight of pure
`PLA samples.
`
`KASHIV1050
`IPR of Patent No. 9,492,392
`
`

`

`546
`
`:E
`Cl
`·o;
`~
`
`120000
`
`100000
`
`3,500 Mw: no thermal treatment
`•
`[] 3,500 Mw: 60°C/24 hr thermal treatment
`II 92 000 Mw: no thermal treatment
`8 92,000 Mw: 60°C/24 hr thermal treatment
`
`u
`
`E
`
`.. 0
`~ '" :;
`.. Cl
`'" iii
`> '" :E
`
`Cl
`·o;
`:;1:
`
`80000
`
`60000
`
`40000
`
`20000
`
`0
`
`PLA Extracted From Tablet
`Pure PLA
`Fig. 4. Influence of thermal treatment on the molecular weight of
`pure PLA (3500 and 92,000 Mwl and PLA extracted from tablets.
`
`from both thermally and non-thermally treated tablets were
`also tested using DSC. As seen by the transition midpoints of
`the tablet samples in Fig. 6, thermal treatment had no effect
`on the Tg in the tablet samples containing the 138,000 Mw
`PLA. The results also showed that the Tg of the tablet sam-
`ples was unchanged compared to the Tg of the pure polymer
`samples. The DSC analysis was also performed on other
`tablet samples containing the remaining Mw grades of PLA,
`with no significant differences in Tg between the samples of
`pure polymer, as well as those from tablet samples contain-
`ing PLA. These results indicated that the Tg was unaffected
`by thermal treatment. In addition, the Tg of the pure PLA
`was not influenced by combining the polymer with the other
`formulation components or by the processing conditions
`used in tablet manufacturing.
`
`Omelczuk and McGinity
`
`The results in Fig. 7 show the dissolution profiles of
`tablets containing aqueous dispersions of PLA before and
`after thermal treatment. In contrast to the method of prepar-
`ing granulations with organic solutions of PLA, a portion of
`the granulation utilizing the aqueous dispersions of PLA was
`dried at 60°C for 1 hr prior to tablet compression. Without
`any heat drying of the granulation, the drug release from
`tablets using the aqueous dispersion of PLA was signifi-
`cantly faster than that of the tablets using organic solutions,
`as well as that of tablets prepared from a granulation that
`was heat dried. This relative accelerated drug release was
`supported by the physical observation of the tablets, which
`showed a substantial amount of swelling and fragmentation
`of the tablet matrix during dissolution. This effect could be
`attributed to the residual amount of surfactant in the
`pseudolatex formulation, which may have enhanced the wa-
`ter penetration and diffusion of drug into the compact. In
`addition, incomplete coalescence of the polymeric nanopar-
`ticles in the pseudolatex could have also resulted in weaker
`polymer films and an acceleration in the rate of drug release.
`The drying of the PLA granulation above the Tg of the poly-
`mer enhanced the coalescence ofthe PLA particles, which in
`turn strengthened the matrix and retarded the drug release.
`In this case, tablets made from cured granulations demon-
`strated a drug release profile which was consistent with that
`of tablets utilizing organic solutions of PLA. During coales-
`cence, the evaporation of the water forced the fusing of in-
`dividual polymer particles to form a continuous network of
`polymer in the tablet matrix. This process requires a mini-
`mum film-forming temperature above which a continuous
`film is formed, and which is often the Tg of the polymer (27).
`Thermal treatment of tablets prepared from aqueous
`pseudolatex dispersions of PLA whose granulations were
`heat-dried showed a reduction in the drug release which was
`
`DSC
`
`Scanning Rata: 20.0 DEGJMIN
`
`-
`
`Poly(d,l·lac:tlc acid) I
`
`PLA: no therm~~l lrNtment
`
`PLA: 60"C/24hr
`
`thenMI trHtiMnl
`
`1 00'!1.
`
`theopllylllne
`
`100% mlcrocryataHine e.lluloH
`
`Tablet: no thermal trNtment
`
`T1blet:
`
`IO"C/24hr
`
`thermol trNI,_,t
`
`
`
`r-.....__ ________ _
`
`I
`290
`
`300
`
`310
`
`320
`TEMPERATURE (K)
`Fig. 5. Influence of thermal treatment on the glass transition temperature of PLA using
`DSC.
`
`I
`330
`
`340
`
`350
`
`KASHIV1050
`IPR of Patent No. 9,492,392
`
`

`

`Physical-Mechanical and Dissolution Properties of Poly(oL-Lactic Acid)
`
`547
`
`Poly(d,l-lactlc acid)
`
`DSC
`
`Scanning Rate: 20.0 DEGIMIN
`
`(3,50011wl
`PLA
`no thermal treatment
`
`(3,50011•1
`PLA
`&O•C/24hr
`thermal
`
`treatment
`
`(138,00011wl
`PLA
`no thermal treat .. nt
`
`(131,00011wl
`PLA
`&o•CJ24hr
`therm11
`
`treatment
`
`290
`
`300
`
`310
`
`320
`TEMPERATURE (K)
`Fig. 6. Influence of thermal treatment on the glass transition temperature of pure PLA
`(138,000 Mw) and that extracted from tablets containing PLA.
`
`330
`
`340
`
`350
`
`comparable to the retardation demonstrated by tablets using
`organic solutions of PLA. The thermally treated tablets ap-
`peared to be less swollen and demonstrated less surface de-
`fects than non-thermally treated tablets. However, thermal
`treatment had a much larger effect on retarding the drug
`release for tablets whose granulations were not cured (Fig.
`7). After 6 hr, the non-thermally treated tablets had already
`broken apart and released 100% theophylline, while the in-
`tact thermally treated tablets had released only 50% drug.
`The extent of this retardation was equivalent to that of ther-
`mally treated tablets whose granulation was dried above the
`
`100
`
`80
`
`60
`
`40
`
`20
`
`"0
`Gl
`Ill as
`Gl
`Gi
`a:
`Gl
`.!:
`>.
`.c a.
`0
`Gl
`.c
`1-
`:.!! 0
`
`!
`
`0
`0.0
`
`.......... ~:::t
`
`~;.::---····
`..................
`
`---o--
`no thermal treatment
`·····•····· 60°C, 24 hr thermal treatment
`-..- no thermal treatment ••
`
`----~--·· 60°C thermal treatment••
`•• Heat-Dried Granulation
`
`2.0
`
`4.0
`
`6.0
`
`8.0
`
`10.0
`
`12.0
`
`(hr)
`Time
`Fig. 7. Effect of thermal treatment on the drug release from tablets
`utilizing aqueous dispersions of PLA (92,000 Mw).
`
`Tg of the PLA. Thus, in addition to promoting a better dis-
`tribution of polymer throughout the matrix and increasing
`the bonding strength, these results suggest that thermal
`treatment of the tablet matrix also strengthened the polymer
`network by ensuring complete coalescence of the PLA par-
`ticles from the aqueous dispersion.
`In conclusion, thermal treatment above the Tg of PLA
`significantly improved the polymer network and retarded the
`drug release of matrix tablets containing PLA as a retardant
`polymer. Thermal treatment also improved the compaction
`properties of the formulations, while not affecting the Mw
`and the Tg of the PLA. These results were supported by
`general principles on annealing of polymers. These results
`also demonstrated that thermal treatment or any heating pro-
`cesses can profoundly affect the physical-mechanical prop-
`erties of formulations containing polymers, especially in ap-
`plications utilizing aqueous pseudolatexes of polymers.
`
`ACKNOWLEDGMENTS
`The authors wish to thank the FMC Corporation in
`Princeton, NJ, for their financial support, as well as the
`Pharmaceutical Manufacturers Association (PMA) Founda-
`tion for the predoctoral fellowship in pharmaceutics awarded
`to Marcelo Omelczuk.
`
`REFERENCES
`1. L. Nielson. Mechanical Properties of Polymers and Compos-
`ites, Marcel Dekker, New York, 1974, pp. 139-229.
`2. Encyclopedia of Polymer Science and Engineering, Vol. 2. An-
`ionic Polymerization and Cationic Polymerization, John Wiley
`and Sons, New York, 1985, pp. 43-53.
`3. S. Porter. The use of Opadry, Coateric and Surelease in the
`aqueous film coating of pharmaceutical oral dosage forms. In
`J. W. McGinity (ed.), Aqueous Polymeric Coatings for Phar-
`
`KASHIV1050
`IPR of Patent No. 9,492,392
`
`

`

`548
`
`Omelczuk and McGinity
`
`maceutical Dosage Forms, Marcel Dekker, New York, 1989,
`pp. 317-362.
`4. M. R. Harris, I. Ghebre-Sellassie, and R. U. Nesbitt. A water-
`based coating process for sustained release. Pharm. Tech.
`10(9):102-107 (1986).
`5. T. Wheatly. Applications of Aquacoat ethylcellulose aqueous
`disperions for sustained release. In Y. Kaweshima (ed.), Recent
`Advances on Aqueous Polymeric Coating System and Related
`Techniques, Proceedings of the Pre World Congress, Particle
`Technology, Gifu, Japan, Sept. 1990, pp. 11-17.
`6. B. H. Lippold, B. K. Sutter, and B. C. Lippold. Parameters
`controlling drug release from pellets coated with aqueous ethyl
`cellulose dispersions. Int. J. Pharm. 54:15-25 (1989).
`7. I. Ghebre-Sellassie, U. Iyer, D. Kubert, and M. B. Fawzi.
`Characterization of a new water-based coating for modified-
`release preparations. Pharm. Tech. 12(9):96--106 (1988).
`8. E. S. Ghali, G. H. Klinger, and J. B. Schwartz. Thermal treat-
`ment of beads with wax for controlled release. Drug Dev. Ind.
`Pharm. 15:1311-1328 (1989).
`9. M. 0. Omelczuk and J. W. McGinity. The influence of polymer
`glass transition temperature and molecular weight on the drug
`release from tablets containing poly(oL-lactic acid). Pharm.
`Res. 9:26--32 (1992).
`10. M. 0. Omelczuk. An Investigation of the Chemical, Physical-
`Mechanical, and Dissolution Properties of Controlled Release
`Tablets Containing Poly( d,l-lactic acid), Ph.D. dissertation,
`University of Texas at Austin, Austin, 1991.
`ll. M. Coffin and J. W. McGinity. Biodegradable pseudolatexes:
`The chemical stability of poly(DL-lactide) and poly(e-
`caprolactone) nanoparticles in aqueous media. Pharm Res.
`9:200-205 (1992).
`12. M. Coffin. The Development and Physical-Chemical Properties
`of Biodegradable Pseudolatexes and Their Application to Sus-
`tained Release Drug Delivery Systems, Ph.D. dissertation, Uni-
`versity of Texas at Austin, Austin, 1990.
`13. E. N. Hiestand, J. E. Wells, C. B. Poet, and J. F. Ochs. Phys-
`ical process of tableting. J. Pharm. Sci. 66:510-519 (1977).
`14. E. N. Hiestand and D.P. Smith. Indices of tableting perfor-
`mance. Powder Techno/. 38:145 (1984).
`15. E. N. Hiestand. The basis for practical applica