AAPS PharmSciTech, Vol. 11, No. 1, March 2010 ( # 2010)
`DOI: 10.1208/s12249-010-9378-z
`
`Research Article
`
`Effects of Thermal Curing Conditions on Drug Release from Polyvinyl
`Acetate–Polyvinyl Pyrrolidone Matrices
`
`Hatim S. AlKhatib,1,4 Saja Hamed,2 Mohammad K. Mohammad,1 Yasser Bustanji,1 Bashar AlKhalidi,1
`Khaled M. Aiedeh,1 and Samer Najjar3
`
`Received 13 September 2009; accepted 9 January 2010; published online 20 February 2010
`Abstract. This study aimed to investigate the effects of dry and humid heat curing on the physical and
`drug release properties of polyvinyl acetate–polyvinyl pyrrolidone matrices. Both conditions resulted in
`increased tablet hardness; tablets stored under humid conditions showed high plasticity and deformed
`during hardness testing. Release from the matrices was dependent on the filler's type and level. Release
`profiles showed significant changes, as a result of exposure to thermal stress, none of the fillers used
`stabilized matrices against these changes. Density of neat polymeric compacts increased upon exposure
`to heat; the effect of humid heat was more evident than dry heat. Thermograms of samples cured under
`dry heat did not show changes, while those of samples stored under high humidity showed significant
`enlargement of the dehydration endotherm masking the glass transition of polyvinyl acetate. The change
`of the physical and release properties of matrices could be explained by the hygroscopic nature of
`polyvinyl pyrrolidone causing water uptake; absorbed water then acts as a plasticizer of polyvinyl acetate
`promoting plastic flow, deformation, and coalescence of particles, and altering the matrices internal
`structure. Results suggest that humid heat is more effective as a curing environment than dry heat for
`polyvinyl acetate–polyvinyl pyrrolidone matrices.
`KEY WORDS: aging; drug release; physical stability; polyvinyl acetate–polyvinyl pyrrolidone;
`pycnometric density; thermal curing.
`
`INTRODUCTION
`
`The success of the process of development of a drug
`delivery system (DDS) is highly dependent on the appro-
`priate selection and processing of a carrier material capable
`of exerting the desired control on the onset and rate of drug
`delivery (1).
`A significant proportion of carriers in oral DDSs are
`polymeric materials fabricated in matrix-type systems. A
`matrix device is a simple design consisting of a drug dispersed
`and/or dissolved homogenously throughout a polymeric
`matrix (1,2). This simple, but adaptable, design allows a
`polymer-based matrix DDS to deliver wide variety of drugs
`at controlled rates. In addition, the ease of manufacture,
`versatility, cost-effectiveness, and the fact that dose dumping
`is a highly unlikely event, since the drug is dispersed
`homogenously in the matrix, contribute to matrix-type
`in the field of
`devices being amongst the most successful
`drug delivery.
`In such systems, drug release is preceded by the
`penetration of the dissolution medium into the porous matrix
`
`1 Faculty of Pharmacy, University of Jordan, Amman 11942, Jordan.
`2 Faculty of Allied Health Sciences, The Hashemite University, Zarqa
`13115, Jordan.
`3 Sana Pharmaceutical Research Co., Amman 11171, Jordan.
`4 To whom correspondence should be addressed. (e-mail: h.khatib@ju.
`edu.jo)
`
`to dissolve the drug, followed by diffusion of the dissolved
`molecules out of the matrix.
`An erosional component may be present and contribu-
`ting significantly to the drug release depending on the
`solubility-swelling properties of the polymer, the degree of
`agitation and composition of the dissolution medium, and the
`type and level of filler excipients used (3–5).
`The use of polymeric materials in sustained/controlled
`drug delivery is best exemplified by hydroxypropyl methyl-
`cellulose (HPMC) which is probably the most commonly used
`matrix former in pharmaceutical formulations (6).
`Other matrix formers include carbomers (7), ethyl
`cellulose and related derivatives (8), methacrylate esters
`copolymers (9), and various natural gums (10).
`The co-processed excipient, Kollidon® SR, is probably
`the latest addition to the limited list of commercially available
`matrix formers. It is a co-processed polymeric combination
`consisting of 80% polyvinyl acetate (PVAc) having a molecular
`weight of about 450,000 and 19% polyvinyl pyrroloidone (PVP)
`Ph.Eur./USP (Kollidon® 30). About 0.8% of sodium lauryl
`sulfate and about 0.6% of silica are used as stabilizers (11).
`PVAc–PVP-based matrices were found to provide sus-
`tained release of model compounds. Certain formulation and
`processing variables were found to play an important role in
`controlling release kinetics, such variables include the com-
`pression force, drug loading, level of the polymeric material
`in the matrix, excipient level, as well as the nature of the
`excipients (water soluble vs. water insoluble) (12,13).
`
`253
`
`1530-9932/10/0100-0253/0 # 2010 American Association of Pharmaceutical Scientists
`
`KASHIV1042
`IPR of Patent No. 9,492,393
`
`

`

`254
`
`On the other hand, sensitivity of PVAc–PVP-based tablets
`to temperature and humidity has been pointed out in the phar-
`maceutical literature. One group (13) reported a decrease in the
`dissolution rate along with an increase in hardness of diphen-
`hydramine HCl tablets prepared with a high level of PVAc–PVP
`without diluents or with 15% diluent (lactose, Emcompress®)
`and subjected to accelerated stability conditions. At higher
`levels of Emcompress® (25%), no changes occurred (13).
`Another group (14) reported that PVAc–PVP-based
`tablets demonstrated reproducible drug release patterns
`when stored at 25°C/60% RH and 30°C/70% RH for up to
`6 months. On the other hand, drug release from matrix
`tablets stored at 40°C/75% RH decreased slightly (14). A
`similar observation was made with PVAc–PVP mini-tablets
`stored under the same conditions (15).
`Since the stability of the performance of a DDS during
`long storage periods is one of the most important considerations
`in choosing a carrier material, this physical aging phenomenon
`constitutes an important limitation to the use of PVAc–PVP as a
`controlled release matrix former despite it having excellent
`flow, compression, and release-controlling properties.
`Drug release from systems susceptible to such a thermal-
`aging phenomenon has been stabilized using post-processing
`thermal treatment or curing (16–18). Curing involves the
`exposure of the dosage form (matrix system or polymer coated
`reservoir system) to temperatures above the glass transition
`temperature (Tg) of the polymeric component for a determined
`period of time so that adjacent polymer chains and segments
`can diffuse past each other leading to coalescence of polymeric
`particles producing a more homogenous, less porous system.
`A post-compression curing step was suggested to stabi-
`lize drug release from PVAc–PVP matrices (13). However,
`only dry heat was used for curing and used at one level only
`(60°C), the inadequacy of such a condition has been pointed
`out by the same group (19) where they reported that it was
`found; as a result of a stability chamber malfunction whereby
`the temperature had temporarily reached 90°C; that tablets
`were further strengthened into a hardness range beyond the
`readout capacity of a typical hardness tester.
`This gap in our knowledge of optimal curing procedures
`for PVAc–PVP matrices has prompted us to investigate the
`effects of exposure to elevated temperature with or without
`humidity, as candidates for curing conditions, on the drug
`release and physical properties of PVAc–PVP matrices
`prepared using different filler excipients.
`Our study also aimed to understand the mechanisms
`mediating such an effect to allow formulation scientists to
`rationally suggest suitable curing conditions and formulation
`components necessary to ensure the stability of the quality of
`PVAc–PVP containing formulations.
`
`MATERIALS AND METHODS
`
`Materials
`
`Chlorpheniramine maleate (CPM), C16H19ClN2, was
`used as a water-soluble model drug and was generously
`donated by United Pharmaceutical Manufacturing Co. Ltd.,
`(Amman, Jordan).
`PVAc–PVP-based excipient, Kollidon® SR (lot:
`69982988Q0), was generously donated by BASF (Germany);
`
`AlKhatib et al.
`
`microcrystalline cellulose (MCC), Avicel PH-101® (lot:
`249557 186), was purchased from FMC (Switzerland); anhy-
`drous dibasic calcium phosphate (DCP;
`lot: 73218/1), was
`purchased from Janssen Chimica (Belgium); D (+)-lactose
`monohydrate (LAC; lot. and filling code: 436197/112303242),
`was purchased from Fluka BioChemika (Switzerland); colloi-
`dal silica powder, Aerosil® (lot: 9888370), was purchased
`from BDH chemicals Ltd (England); and magnesium stearate
`was purchased from Unichema International (Malaysia).
`
`Methods
`
`Tablet Preparation
`
`PVAc–PVP matrix tablets with a target weight of 300 mg
`and CPM content of 20 mg were prepared by direct
`compression. The formulation composition is shown in
`Table I. Twelve different formulations were prepared using
`different weight ratios (8:2, 6:4, 4:6, and 2:8) of PVAc–PVP to
`specific filler excipients (MCC, DCP, and LAC).
`The formulas were labeled using the letters LAC, MCC,
`or DCP indicating the type of diluent used in combination
`with the numbers 8:2, 6:4, 4:6, or 2:8 to denote the weight
`ratio of PVAc–PVP to the specific diluent.
`CPM, PVAc–PVP, the specific filler excipients used (LAC,
`MCC, or DCP), and colloidal silica were passed through a 25-
`mesh sieve (710 μm) and then blended manually in a plastic
`bag for 10 min. Afterwards, Mg stearate, sieved through a 25-
`mesh sieve, was added and mixed for an additional 2 min.
`The blend was compressed on a Manesty Model F single
`punch tableting machine (Thomas Engineering Inc., Hoffman
`Estates, IL, USA) using 9 mm round-shaped flat punches to a
`target tablet hardness of 100–200 N.
`Neat PVAc–PVP tablets were prepared in order to study
`the physical properties and response to thermal curing of a
`PVAc–PVP matrix without interference from the fillers. The
`neat PVAc–PVP tablets were prepared by compressing accu-
`rately weighed 300 mg portions of PVAc–PVP using 9 mm
`round-shaped flat punches in a hydraulic press (Karl Kolb,
`Germany) at a compression force of 10 kN for 10 s. The punches
`were lubricated with 5% (w/v) magnesium stearate suspension
`in methanol before each compression and allowed to dry.
`
`Exposure to Thermal Stress Conditions
`
`Tablets from the 12 prepared formulas were put in open
`Petri dishes and split in two groups. The first group was
`placed in a stability chamber (Binder KBF 240, Binder,
`Germany) pre-equilibrated to 60°C/75% RH. The second
`
`Table I. Formulation Composition of Polyvinyl Acetate–Polyvinyl
`Pyrroloidone-Based Tablets
`
`Component
`
`Milligrams/tablet
`
`Percentage
`
`Chlorpheniramine maleate
`Colloidal silicon dioxide
`Magnesium stearate
`PVAc–PVP + filler excipient
`Total
`
`20
`3
`3
`274
`300
`
`6.67
`1.00
`1.00
`91.33
`
`KASHIV1042
`IPR of Patent No. 9,492,393
`
`

`

`Effects of Thermal Curing on PVAc – PVP Matrices
`
`255
`
`dissolved drug through a reasonably intact matrix. Although
`the model may be less than ideal for describing a “real”
`matrix system, it is still considered the most famous and most
`often used mathematical equation to describe the release rate
`of drugs from such systems. This is probably due to its
`simplicity in describing the release process using a single
`value of the apparent release rate constant (21).
`This simplicity is of great value in our situation where we
`are not interested in the mechanism of the drug release as we
`are in a quantitative measure of the drug release in the form
`of an apparent release rate constant.
`The percentage change in the apparent release rate
`constant after storage under elevated temperature conditions
`was calculated according to Eq. 2.
`$k %ð
`
`
`
` 100
`
`ð2Þ
`
`
`Þ ¼ kt kf
`
`kf
`
`group was placed in a dry heat oven at 60°C (Philip Harris
`Ltd, Shenstone, England).
`At predetermined time points (1 day, 4 days, 1 week,
`2 weeks, 1 month, 2 months, and 3 months), samples of
`tablets were collected and stored in closed glass bottles for
`dissolution testing and hardness measurements.
`Weight measurements were performed on the same set
`of 20 tablets from each formula throughout the study.
`Dissolution testing, weight, and hardness measurements
`were performed after the tablets were allowed to cool down
`to room temperature.
`Neat PVAc–PVP tablets and PVAc–PVP powder were also
`stored under the abovementioned thermal conditions for periods
`up to 1 month. At predetermined time points (1 day, 1 week, and
`1 month), samples were withdrawn for density measurements
`using helium pycnometry and thermal analysis using differential
`scanning calorimetry (DSC).
`
`Tablet Testing
`
`Tablet weight variation. Twenty tablets from each formula
`were selected, individually weighed (Shimadzu AY120 analytical
`balance, Japan), put in open Petri dishes, and placed under
`thermal stress conditions (previous section). At predetermined
`time points (previous section), the tablets were withdrawn and
`reweighed. The average weights and standard deviations were
`calculated.
`
`Tablet hardness. Hardness was determined for ten tablets
`(of known weights) of each formula at zero time and at
`predetermined time points during the thermal stress studies
`(previous section) using Dr. Schleuniger Hardness tester
`(Schleuniger Pharmatron AG, Solothurn, Switzerland). The
`average hardness and standard deviation were calculated.
`
`Tablet dissolution testing. Dissolution studies were con-
`ducted in a USP dissolution apparatus II (Erweka DT600,
`Germany) over a 12-h period using 900 mLs of deionized
`water as dissolution medium. The stirring rate and temper-
`ature were adjusted to 100 rpm and 37±0.5°C, respectively.
`At predetermined time intervals, 5 mL samples were
`withdrawn for analysis and immediately replaced with an
`equal volume of fresh medium maintained at
`the same
`temperature. Samples were filtered using 0.45 μm syringe
`filters before the absorbance of CPM was measured at
`261 nm (SpectroScan® 80D, SpectroScan, USA). CPM
`concentration was calculated from linear calibration plots.
`The dissolution tests were performed in triplicates, and the
`mean values as well as standard deviations were calculated.
`In order to quantify the changes in the drug release
`profiles as a function of the duration and type of thermal
`exposure, the release profiles were fitted to the Higuchi
`square root of time model (20) given in Eq. 1:
`¼ kt0:5
`
`ð1Þ
`
`Mt
`M1
`
`where Mt/M∞ is the fraction of drug released at time t, and k
`is the apparent release rate constant.
`One of the most important assumptions in the Higuchi
`model is that the only release mechanism is diffusion of the
`
`where kt is the apparent release rate constant from tablets
`stored for time t, and kf is the apparent release rate constant
`from freshly prepared tablets.
`
`Differential Scanning Calorimetry
`
`The evaluation of the thermal properties was performed
`on PVAc–PVP powder and neat PVAc–PVP tablets after
`storage, gently triturated in a porcelain mortar, using Mettler
`Toledo DSC 823 (Mettler, Switzerland).
`Samples (4–5 mg) were weighed and sealed into
`aluminum pans with pierced lids. The samples were heated
`from 25°C to 250°C at a heating rate of 10°C/min under
`nitrogen purge (80 ml/min).
`
`Helium Pycnometry
`
`Density measurement of neat PVAc–PVP tablets was
`carried out using Ultrapycnometer 1000 (Quantachrome Instru-
`ments, USA). Before use, the instrument was allowed a minimum
`of 1 h for warm-up and thermal equilibration; a circulating water
`bath was used to provide constant temperature conditions (25°C).
`The instrument was calibrated before measurements
`using a small calibration sphere (volume, 7.0699 cm3 in a
`sample holder with a nominal volume of 10.8 cm3).
`For measurement, three to four neat PVAc–PVP tablets
`were weighed using an analytical balance (SHIMADZU
`AY120, Japan) then placed in the sample cell after removing
`the calibration sphere, a minimum of six runs were used to
`obtain accurate results, and averages and standard deviations
`were calculated. The same procedure was applied to PVAc–
`PVP powder.
`
`RESULTS AND DISCUSSION
`
`Tablets were successfully prepared from all of the pre-
`pared formulations. Due to different compaction properties of
`the used filler excipients, it was decided not to use a constant
`compression force for the preparation of the tablets but instead
`targeting an acceptable level of hardness (between 100 and
`200 N). Tablets of consistent target hardness were most
`successfully prepared when LAC was used as a filler excipient,
`while in tablets containing MCC or DCP as fillers, the hardness
`
`KASHIV1042
`IPR of Patent No. 9,492,393
`
`

`

`256
`
`AlKhatib et al.
`
`decreased with increasing the content of the filler excipient in
`the mixture even when using high compression forces.
`The prepared tablets were then placed under humid or
`dry thermal stress conditions (60°C/75% RH and 60°C,
`respectively). These are relatively harsher conditions than
`the ones usually used for the curing of film coatings; however,
`they were decided upon considering the fact that they are
`intended to modify a thick polymeric matrix rather than a
`thin film on the surface of a tablet or a pellet. Interestingly, a
`recent report (22) showed that similar, unconventionally
`
`harsh, curing conditions (60°C/75% RH or 80°C) were
`successful
`in improving the storage stability of Aquacoat-
`coated pellets at accelerated stability test conditions in
`comparison to other “milder” curing conditions.
`
`Tablet Weight and Hardness
`
`Figure 1 shows the percentage change in the tablet
`weight as a function of thermal exposure time under dry and
`humid conditions.
`
`Fig. 1. Effect of storage under dry heat (60°C) and humid heat (60°C/75% RH) conditions on the
`weight change of polyvinyl acetate–polyvinyl pyrroloidone-based tablets
`
`KASHIV1042
`IPR of Patent No. 9,492,393
`
`

`

`Effects of Thermal Curing on PVAc – PVP Matrices
`
`257
`
`Tablets exposed to dry heat conditions showed a
`reduction in their mass corresponding to removal of residual
`moisture associated with the tablet components. This process
`of weight loss is fastest in the early stages of thermal exposure
`reaching an average value for all formulations of 66.49%
`(±7.03) and 82.85% (±7.53%) of the 90-day (plateau) level
`after 1 and 4 days, respectively.
`On the other hand, tablets stored under high temperature
`and humidity conditions showed an increase in their weight with
`time as a result of water sorption. Similar to the weight loss
`process, the tablets showed a quick weight gain in the early
`stages of exposure to high humidity with an average weight gain
`for all formulations reaching 86.98% (±3.91) and 90.48% (±4.59)
`of the 60-day (plateau) level after 1 and 4 days, respectively.
`In addition, the weight gain seems to show a direct linear
`relationship with the content of PVAc–PVP in the tablet
`formulations as can be seen in Fig. 2. The linear relations
`have R2 values of 0.9905, 0.9825, and 0.9912 for matrices
`prepared using MCC, DCP, and LAC as filler excipients.
`This points to PVAc–PVP as the main water sorping
`component of
`the tabletted formulas which is expected
`based on the high hygroscopicity of the PVP component in
`PVAc–PVP (23,24).
`These results are in agreement with the previous reports
`where tablets with highest level of PVAc–PVP exhibited
`greatest moisture uptake (19).
`Tablets prepared with DCP as a filler excipient showed
`the smallest percentage weight gain in comparison to those
`prepared with MCC and LAC, this may be explained by the
`nonhygroscopicity of DCP in comparison to the hygroscopic
`MCC and LAC.
`In regards to the tablet hardness, the storage under dry
`heat resulted in an increase in the tablet hardness as can be
`seen in Fig. 3. The increase in the tablet hardness was related
`
`directly to the PVAc–PVP content in the tablets indicating
`that a change in the structural properties in the PVAc–PVP
`component of the matrix is responsible for the increased
`mechanical strength of the tablets.
`However, the most pronounced change in hardness was
`observed in the case of the tablets stored under elevated
`temperature and humidity conditions. Tablets with high
`PVAc–PVP content exposed to high temperature and humid-
`ity conditions for periods as short as 1 day showed increased
`hardness and exhibited pronounced elasticity; no reading was
`recorded by the hardness tester for those tablets.
`The change in tablet hardness as a function of the
`storage time under humid heat conditions is shown in Fig. 4.
`
`Differential Scanning Calorimetry
`
`DSC was used to detect possible changes in the glass
`transition of the rate controlling PVAc component of Kolli-
`don® SR which is expected to contribute to the molecular
`mobility of polymeric chains, plastic flow of polymeric
`particles, internal structural changes, as well as hardness and
`drug release changes of the Kollidon® SR matrices.
`Fresh samples of PVAc–PVP powder showed a distinc-
`tive endothermic peak at around 40°C followed by a broad
`peak extending from around 50°C to 100°C. This observation
`is in accordance with the reported behaviors of the two
`polymeric components of the polymeric system with the first
`one corresponding to the glass transition temperature of
`PVAc (11,25,26) and the second one corresponding to
`dehydration of the hygroscopic PVP.
`The thermograms of PVAc–PVP powder samples stored
`in open containers at 60°C for periods up to 1 month (Fig. 5)
`did not show significant change as expected.
`
`Fig. 2. Effect of polyvinyl acetate–polyvinyl pyrroloidone content on the average weight gain by
`tablets stored under high temperature–high humidity conditions (60°C/75% RH)
`
`KASHIV1042
`IPR of Patent No. 9,492,393
`
`

`

`258
`
`AlKhatib et al.
`
`Fig. 3. Effect of storage under dry heat (60°C) on the hardness of polyvinyl acetate–polyvinyl
`pyrroloidone-containing tablets
`
`On the other hand, PVAc–PVP powder stored in open
`containers placed in a stability chamber at 60°C and 75% RH
`showed a significant
`increase in the size of
`the PVP
`dehydration peak corresponding to increased energy invest-
`ment in the removal of sorped water.
`Unfortunately, this increase in the dehydration isotherm
`masked the PVAc glass transition, making it impossible to
`detect the plasticization effect of sorped water. However, the
`plasticization effect of water on PVAc has been reported for
`polymeric composites of PVAc and polystyrene (27).
`
`The plasticization of PVAc in our case would be a direct
`result of our earlier observation of moisture uptake and a major
`component of the contribution of the hygroscopic PVP to the
`change in the structural properties of the PVAc–PVP matrices.
`
`Helium Pycnometry
`
`The density of fresh PVAc–PVP powder was determined
`by helium pycnometry to be 1.3099±0.011 g/cm3 (average ±
`standard deviation); upon compressing the PVAc–PVP
`
`KASHIV1042
`IPR of Patent No. 9,492,393
`
`

`

`Effects of Thermal Curing on PVAc – PVP Matrices
`
`259
`
`Fig. 4. Effect of storage under humid heat (60°C/75% RH) on the hardness of polyvinyl acetate–
`polyvinyl pyrroloidone-based tablets
`
`powder to produce neat PVAc–PVP tablets, the density
`dropped to 1.1997±0.002 and 1.1789±0.001 g/cm3 for two
`different sets of six units each. This is explained by the
`formation of dead spaces within the tablet matrix that could
`not be penetrated by helium during the pycnometric
`measurements resulting in higher apparent volume and
`lower density. The former set (initial density of 1.1997±
`0.002 g/cm3) was then stored under humid heat conditions,
`and the latter (initial density of 1.1789±0.001 g/cm3) was
`stored under dry heat conditions.
`
`The results of density measurements after storage of the
`two tablet sets under dry and humid heat are shown in
`Table II.
`Tablets stored under humid heat conditions showed a
`reduction in density after 1 day followed by a gradual
`increase in density with prolonged exposure to humid heat.
`A qualitatively similar observation can be made with the
`set of tablets stored under dry heat conditions, which showed
`a reduction in its density upon storage for 1 day followed by a
`gradual increase with prolonged storage time.
`
`KASHIV1042
`IPR of Patent No. 9,492,393
`
`

`

`260
`
`AlKhatib et al.
`
`The initial reduction in density is most probably due to
`the decompression and the elastic recovery of the tablets
`(28,29). On the other hand, the following increase in density
`upon prolonged storage is a reflection of changes in internal
`structure of the neat PVAc–PVP tablets matrix that is brought
`about by the plastic flow of the PVAc–PVP component within
`the tablet matrix encouraged by the elevated heat of storage.
`In addition, the results show a difference in the response
`of the neat PVAc–PVP tablets when stored under different
`thermal stress conditions with the humid heat exerting a more
`pronounced effect on the density than the dry heat which
`could be explained by the plasticizing effect of water in the
`matrix allowing for easier rearrangement of the polymeric
`network by plastic flow.
`
`Table II. Effect of Storage under Dry Heat (60°C) and Humid Heat
`(60°C/75% RH) Conditions on the Density (g/cm3) of Neat Polyvinyl
`Acetate–Polyvinyl Pyrroloidone Compacts
`
`Density (g/cm3; average ± SD)
`
`Fresh
`Storage
`1 day
`2 days
`4 days
`1 week
`2 weeks
`1 month
`
`1.1997(±0.0010)
`60°C±75% RH
`1.1237 (±0.0117)
`1.1335 (±0.0078)
`1.1916 (±0.0093)
`1.1907 (±0.0099)
`1.2604 (±0.0499)
`1.2743 (±0.0088)
`
`1.1789(±0.0010)
`60°C
`1.0661 (±0.0018)
`1.0715 (±0.0019)
`1.1214 (±0.0197)
`1.0845 (±0.0011)
`1.1157 (±0.0048)
`1.1688 (±0.0033)
`
`Data presented as an average ± SD
`
`Drug Release and Modeling
`
`The amorphous nature of PVAc coupled with its low Tg
`of ≈35°C (11) imparts certain unique characteristics to this
`polymeric matrix. Upon compression, an insoluble plastic
`PVAc matrix structure is formed. The drug release from such
`a structure depends on the diffusion of the dissolved drug
`through channels created by the gradual
`leaching of the
`water-soluble PVP component. The presence of filler exci-
`pients with different water solubility/swellability can modu-
`late release profiles from matrix systems.
`
`Fig. 5. Differential scanning calorimetry thermograms of polyvinyl
`acetate–polyvinyl pyrroloidone powder stored under dry heat (60°C)
`or humid heat conditions (60°C/75% RH)
`
`The addition of water-soluble fillers like lactose was
`reported to accelerate the dissolution of soluble drugs by
`decreasing the tortuosity of the diffusion path of the drug (30).
`On the other hand,
`the use of swellable,
`insoluble
`excipients (i.e., MCC or cross-linked carboxymethylcellulose)
`in tablet formulations containing 10% HPMC 2208 has been
`reported to cause an expansion of the gel layer resulting in a faster
`release of an insoluble model drug in the early stages of
`dissolution (burst effect) due to their disintegrating property (31).
`Water insoluble filler excipients, such as DCP, tend to
`slow down drug release from HPMC matrices by getting
`entrapped within the matrix structure increasing the tortuos-
`ity of the matrix (32).
`Figure 6 shows the drug release from freshly prepared
`PVAc–PVP tablets prepared with different excipients. It is
`evident that drug release from PVAc–PVP matrices can be
`modulated easily by changing the type and level of the filler
`excipient.
`Tablets prepared with the highest filler ratio (2:8 series)
`showed a fast release where MCC2:8 was fastest followed by
`LAC8:2, while DCP8:2 was the slowest of the three.
`PVAc–PVP tablets did not gel upon exposure to the
`dissolution medium;
`instead, tablets containing LAC and
`MCC eroded gradually with the rate of erosion being directly
`the filler excipient and
`proportional
`to the content of
`inversely related to the duration of exposure to thermal
`stress. This can be explained based on the nature of these
`fillers being water-soluble (LAC) or water-swellable (MCC).
`On the other hand, the insolubility and nonswellability of
`DCP explain the fact that DCP-containing matrices only
`showed minor erosion at the surface (Fig. 7).
`Figures 8 and 9 show the drug release profiles of
`formulations containing the lowest and highest ratios of
`PVAc–PVP to filler excipients (8:2 and 2:8 formulas) after
`exposure to dry and humid heat for different periods of time.
`These figures show that the change in the release profile
`of the matrices appears to be dependent on the type of
`storage conditions with tablets stored under humid heat
`conditions showing a more pronounced change in their drug
`release in comparison to those stored under dry heat
`the PVAc–PVP content of
`conditions. In addition,
`the
`matrices appears to play an important role with the most
`pronounced changes occurring in matrices with highest
`PVAc–PVP content.
`
`KASHIV1042
`IPR of Patent No. 9,492,393
`
`

`

`Effects of Thermal Curing on PVAc – PVP Matrices
`
`261
`
`Fig. 6. Effect of excipient type and level on drug release from freshly prepared polyvinyl
`acetate–polyvinyl pyrroloidone matrices formulated with lactose, microcrystalline cellulose,
`or dibasic calcium phosphate as filler excipient
`
`These observations are supported by Fig. 10 which shows
`the percentage change in the apparent release constant as a
`function of time of exposure to dry or humid heat of all the
`studied formulas.
`The changes in the apparent rate constants were highest
`in tablets stored under high humidity conditions with the ∆k%
`reaching up to −71.69% and −75.41% after 3 months of
`storage in the case of formulas MCC 8:2 and MCC 2:8.
`The effect of humid heat on matrices with high PVAc–
`PVP content can be explained by the coalescence of
`
`polymeric particle and increased tortuosity of the matrices.
`The increased tortuosity results in increased diffusional path
`length and decreased rate of drug release from the matrix.
`On the other hand, the effect of humid heat on tablets
`with low PVAc–PVP content can only be partially explained
`by the previous mechanism considering its low content of the
`polymeric matrix forming material; however, a more possible
`mechanism involves the action of the coalesced polymeric
`particles as a binding agent
`for the rest of
`the matrix
`components explaining the improved structural integrity of
`
`KASHIV1042
`IPR of Patent No. 9,492,393
`
`

`

`262
`
`AlKhatib et al.
`
`Fig. 7. Photos of polyvinyl acetate–polyvinyl pyrroloidone matrices exposed to (D) dry and (H)
`humid (75% RH) thermal stress (60°C) conditions for periods of 1 h and 1 month after dissolution
`testing for 12 h
`
`the tablets and the hindered erosion or disintegration upon
`exposure to dissolution media resulting in a slower drug
`release which was, otherwise, a relatively quick process
`mediated by tablet disintegration and erosion as can be seen
`in Fig. 7 where formulas MCC 2:8, LAC 2:8, and DCP 2:8
`showed the fastest release in that specific order.
`Both mechanisms are accelerated by the uptake of water
`from the high humidity environment by the hygroscopic PVP
`component of the matrix former and the action of water as a
`plasticizer of the PVAc component. Plasticization of the PVAc
`component allows polymeric chains and segments to diffuse
`past each other crossing particle boundaries and resulting in
`particle bonding and a more tortuous matrix.
`Dry heat resulted in a change in ∆k% reaching up to
`−44.43% and −65.94% after 3 months of storage in the case
`
`of formulas MCC 8:2 and MCC 2:8. Similar scenarios to the
`ones described above are responsible for these changes in
`drug release; however, the absence of the plasticizing effect of
`sorped water slows down these changes.
`It does not appear that the use of one specific filler
`excipient in combination with PVAc–PVP in formulating
`matrices offer much advantages in terms of stabilizing drug
`release upon thermal exposure.
`It should be noted also that thermal stress whether dry or
`humid on drug release achieved most of its effect within the
`first day to the first week of exposure; afterwards, the effect
`reached a plateau. This indicates the potential of a curing step
`for reasonable periods of time (overnight) in stabilizing the
`drug release from PVAc–PVP matrices. However, it should
`be noted that the use of dry heat in the curing step may not
`
`KASHIV1042
`IPR of Patent No. 9,492,393
`
`

`

`Effects of Thermal Curing on PVAc – PVP Matrices
`
`263
`
`Fig. 8. Effect of thermal stress conditions on drug release from matrices containing the
`lowest level of polyvinyl acetate–polyvinyl pyrroloidone (2:8 formulas)
`
`be adequate as the process of aging or maturation of the
`PVAc–PVP matrices was highly dependent on the presence of
`humidity.
`This could point to some formulation approaches that may
`be attempted, besides curing, to stabilize drug release from
`PVAc–PVP matrices including the use of moisture-protective
`coatings. Such approaches should be evaluated as methods of
`optimizing drug delivery using PVAc–PVP systems.
`
`CONCLUSION
`
`The effect of dry and humid thermal stresses, as
`candidates for curing conditions, on the physical and drug
`release properties of PVAc–PVP matrices was investigated.
`Both physical a