PHARMACEUTICAL DEVELOPMENT AND TECHNOLOGY https://doi.org/10.1080/10837450.2018.1469151
RESEARCH ARTICLE
Effect of substitution of plasticizer dibutyl phthalate with dibutyl sebacate on EudragitV RS30D drug release rate control R
Rakesh Singh Chaudhary
, Tejas Patel, Job Richard Kumar and Mohamed Chan
Apotex Inc, Toronto, ON, Canada ABSTRACT
ARTICLE HISTORY
In the current study, the influence of type of plasticizer used with EudragitV RS 30D on the drug release was investigated in solid dosage form extrusion/spheronization, and film coating. The drug pellets were coated for controlling drug release with EudragitV RS 30D containing dibutyl phthalate and compared with dibutyl sebacate as an alternative plasticizer. To study the influence of pH of the dissolution medium on the drug release profile, capsules are tested for drug release profile at pH 1.2, 4.4, and 6.3. Additionally, the aging effect on the curing of EudragitV RS 30D is evaluated by exposing the capsules dosage form to room temperature (25 C ± 2 C/60% ± 5% RH) for time 0, 3, 6, and 9 months, accelerated temperature (40 C ± 2 C/75% ± 5% RH) for time 0, 3, and 6 months, and intermediate temperature (30 C ± 2 C/65% ± 5% RH) for time 0, 6, and 9 months. The replacement of dibutyl phthalate, with dibutyl sebacate for polymer coating system in similar concentration is comparable with respect to plasticization effect. The coalescence of the polymer particles is not changed and requires no additional processing parameter control or additional curing time. R
Received 21 November 2017 Revised 8 February 2018 Accepted 23 March 2018
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KEYWORDS
EudragitV RS 30D; dibutyl phthalate; dibutyl sebacate; methacrylic acid copolymer dispersion; aqueous film coating and aqueous enteric coating R
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Introduction Acrylic Acid polymers are widely used in the film coating of pharmaceutical dosage forms for a variety of functional and nonfunctional usage, e.g. moisture protection, gastric acid resistance, taste masking, and to control the drug release in the controlled release dosage form. For controlling the drug release by barrier film formed on the dosage form consists of film forming polymer, insoluble fillers such as colors, opacifiers, plasticizers, and solvent. For the controlled release dosage form, where the drug release is controlled by the polymer film, use of methacrylic acid derivative is often used. The presence of plasticize in film coating formulations has an important role in providing increased elasticity and flexibility to the film formed (Godwin 2000). The use of plasticizer in polymeric solution or dispersions for film coating allows to increase the workability, flexibility, and reduced tensile strength of the polymer by modifying thermal and mechanical properties of the polymer (Rowe et al. 1984; Bodmeier and Paeratakul 1994). The plasticizers in polymeric dispersion during plasticization, partition into and soften the colloidal polymeric particles and promote particle deformation to enable coalescence into a homogenous film. The plasticization effect is dependent on the plasticizer–polymer compatibility and the plasticizer performance in the film during coating, storage, and during contact with artificial or biological fluids. Plasticizers are water-soluble or water miscible solvents of low volatility. Water soluble plasticizers generally dissolves and the water miscible plasticizers emulsify in the aqueous phase of the dispersion. The integrity of the film is an important factor in controlling the drug release from the drug matrix and the formulation requires optimization to achieve controlled drug delivery consistently. EudragitV RS polymers are widely used as a rate controlling R
CONTACT Rakesh Singh Chaudhary ON, Canada
[email protected]
ß 2018 Informa UK Limited, trading as Taylor & Francis Group
film formers for sustained release dosage forms (Abbaspour et al. 2008; Akhgari et al. 2006). The effect of plasticizer such as, polyethylene glycol and triethyl citrate on the glass transition temperature has been studied with EudragitV RS and reported in the literature (Khodaverdi et al. 2012). Although EudragitV RS 30D dispersion is considered as true latex with lower glass transition (Tg) temperature, the particle coalescences at room temperature is still slow and incomplete. This requires the use of suitable plasticizer to accelerate the particle coalescence at room temperature and reduce curing time (Kibria et al. 2008). The solubility and characteristics of the film produced depends on the type of polymer used for coating pellets or tablets. The EudragitV RS 30D is a 30% aqueous dispersion of a copolymer of acrylic acid and methacrylic acid esters with low content of quaternary ammonium groups (Hogan 2001; Felton and O’Donnell 2008). The quaternary group are present as a salt form which determines the permeability of films formed from the polymer. The film prepared using the EudragitV RS 30D is considered less permeable to water and release the active substances through the diffusion process (Lehmann 1989; Felton and O’Donnell 2008). There are many plasticizers used in the pharmaceutical film coating applications. The amount of plasticizer used in film coating depends on the desired therapeutic system properties related to desired drug release. The substances with low volatility with molecular weight ranging from 200 to 400 such as diesters derived from dicarboxylic acids, e.g. sebacic acid, azelaic acid or from ethylene glycol or propylene glycol, citric acid derivatives (tributyl citrate, triethyl citrate) are very commonly used (Somwanshi et al. 2016). The type of plasticizer used with EudragitV RS 30D determines the intrinsic properties of the film formed by the polymer, and influence on the drug release characteristics by affecting the surface and mechanical properties of the R
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Apotex Inc., Technical Operations – Technical Support Services, 150 Signet Drive, Toronto,
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film coat. The amount and type of plasticizer requires a careful evaluation and consideration as it can greatly influence on the drug release. The film coating process using EudragitV RS 30D polymer dispersion coating solutions requires the appropriate concentration of plasticizer to increase the plasticity of the polymer and to lower the minimum film forming temperature which is approximately 45 C. To achieve lower film forming temperature normally 15–20% of the plasticizer concentration is used with respect to the amount of polymer in coating solution. The use of plasticizer in the amount of 15–20% normally drops the film forming temperature for the EudragitV RS 30D to 35 to 40 C, which is the normal coating temperature in the fluid bed coating chambers. To select a suitable plasticizer system for EudragitV RS 30D, the selection is based on the biocompatibility, compatible with polymer, effect on the drug release, an effect on the mechanical properties, processing characteristics and cost of the coating system. Amongst all the available plasticizers, the most suitable plasticizer is dibutyl phthalate for EudragitV RS 30D polymer coating system. This plasticizer has been used in the pharmaceutical industry for quite some time. Dibutyl phthalate is considered very effective for many synthetic polymer film coating systems and it is used in a very small amount (Rahman and Brazel 2004). The use of dibutyl phthalate with EudragitV RS 30D polymer is to lower the glass transition temperature of the polymer during the coating process to achieve acceptable film on the surface of the substrate being coated. This process follows the ‘Free volume theory’ of plasticization (Marcilla and Beltran 2004). The mechanism of file formation of EudragitV RS 30D polymer depends on the MFT and the film formation process is explained in published literature (Felton and O’Donnell 2008). The use of dibutyl phthalate is well studied and reported in the literature suggesting that its use reduces the brittleness of the synthetic film forming polymers and improved the mechanical properties of the film (Wojciechowska 2012). The animal studies conducted on the use of Phthalates have demonstrated no appreciable toxicity but some phthalates have shown developmental and reproductive toxicity in laboratory animals. The studies show that phthalates are endocrine-disrupting chemicals in animals and may interfere with the production, secretion, transportation, metabolism, receptor binding, mediation of the effects, and excretion of natural hormones that regulate development process and support endocrine homeostasis in the organism. These phthalates are also suspected to have endocrinedisrupting effects in humans, and the level of effect depends on the systemic exposure (Jurewicz and Hanke 2011). Dibutyl phthalate used as plasticizer in the latex polymer based film coating increases the exposure to humans and prolonged exposure have shown to cause decreased sperm counts in male animals and reduced fertility in both female and male animals. Exposure to pregnant animals has resulted in fetal skeletal malformations and decreased anogenital distance in the male offspring (Lehmann et al. 2004). There are limited data available on the effect of dibutyl phthalate exposure to humans and several studies have sought to quantity human exposure to phthalates using measurements of phthalate ester metabolites in urine. The metabolites are excreted rapidly, so urinary levels of phthalate ester metabolites reflect exposure to the parent diester (CDC 2009). Even though the human exposure data available is limited, but U.S. Department of Health and Human Services, Food and Drug Administration and Center for Drug Evaluation and Research (CDER) has determined that there is evidence that exposure to dibutyl phthalate from pharmaceutical present a potential risk of development and reproductive toxicity. Therefore, the Agency recommends to avoid the use of dibutyl phthalate as plasticizer or excipient in CDERR
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regulated drug and biological products. It is recommended to replace the use of dibutyl phthalate in the marketed approved products with suitable alternative plasticizer in the latex-based film coating formulations (FDA 2012). The objective of this study was to evaluate an alternative plasticizer for the film coating formulation containing EudragitV RS polymer dispersion for the drug release coating system for diltiazem hydrochloride controlled release pellets. The effect of substitution of dibutyl phthalate with alternative plasticizer dibutyl sebacate in the same amount will be evaluated to establish that there is no change in the drug release profile for the coated controlled release pellets. The alternative plasticizer dibutyl sebacate for EudragitV RS 30D polymer is selected as it lowers the glass transition temperature of the polymer during the coating process to similar extent as dibutyl phthalate and improves the mechan et al. 2002; Saeltone et al. ical strength of the coating (Zelko 1995). The use of dibutyl sebacate as plasticizer for the brittle polymers is recommended in the range of 5–30% (Nollenberger and Albers 2013). The of dibutyl sebacate as plasticizer for EudragitV RS 30D polymer is related to its effectiveness and influence on the permeability on the film formed. The recommended amount of dibutyl sebacate for EudragitV RS 30D is up to 20% of the dry polymer content (Rowe et al. 1984). The study is designed to identify a suitable replacement of dibutyl phthalate with another plasticizer with similar physical and chemical properties without impacting the performance of the finished product. R
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Materials and methods Materials EudragitV RS 30D and methacrylic acid copolymer dispersion were obtained from Evonik Nutrition & Care GmbH, Darmstadt, Germany, dibutyl phthalate was obtained from Penta manufacturing company, Livingston, NJ, dibutyl sebacate and triethyl citrate were obtained from Vertellus Performance Materials Inc., Greensboro, NC, talc was obtained from Imerys Talc Italy S.p.A., Turin, Italy, diltiazem hydrochloride was obtained from Piramal Enterprises Limited, Digwal Village, Andhra Pradesh, India, methylcellulose was obtained from The Dow Chemical Company, Midland, MI, and Microcrystalline Cellulose was obtained from FMC Corporation health and Nutrition, Little Island Cork, Ireland. R
Methods Preparation of drug base pellets The diltiazem hydrochloride pellets are selected as a model drug for the evaluation purpose. The base pellets were formulated with 90% diltiazem hydrochloride, and 9.2% microcrystalline cellulose passed through quadro comil (Quadro, Colby Drive, Waterloo, Ontario, Canada) fitted with 0.032’R screen (800 mm round opening) into a VG100 Granulator bowl (Glatt Air Techniques Inc., Spear Road, Ramsey, NJ) and mix the blend for 3 to 4 min. The blended mix of powder is wet granulated with 5.0% methylcellulose solution in purified water. The wet mass is passed through Fuzi Paudal Extruder equipped with 1.2 mm screen opening and the extruded material is spheronized in Fuzi Paudal Spheronizer (Fuzi Paudal Co., Ltd., Chuo Joto-ku, Osaka, Japan). The spheronized pellets are dried in Glatt fluid bed processor (Glatt Air Techniques Inc., Spear Road, Ramsey, NJ) at 60 C for 15 min. The dried pellets are sized by passing through two stainless steel screen of 14 mesh screen (1400 mm opening) and collect the pellets on 20 mesh screen (850 mm opening) fitted on Kason shaker (Kason Corporation, East Willow St. Milburn, NJ). The sized pellets
PHARMACEUTICAL DEVELOPMENT AND TECHNOLOGY
are stored in drums, for film coating to obtain coated pellets with desired drug release profiles. The diltiazem base pellet manufacturing process parameters are presented in Table 1. Film coating of drug base pellets The diltiazem hydrochloride drug base pellets are coated with various levels of drug release controlling polymer coating with predetermined drug release profiles. To achieve the final drug release profiles for the diltiazem hydrochloride to release the drug over a period of 24 h is achieved by mixing the three types of coated pellets as a final blend of pellets and filled in empty gelatin capsules according to the dosage form. For the evaluation purpose, the drug pellets are divided into three coating process where the first layer of polymer coating is applied to control the drug release profile and second layer of polymer coating is applied to achieve the acid resistant enteric coating. The first set of drug base pellets is coated as Pellet type – A, Pellet type – B and Pellet type – C with varying amount of drug release controlling polymer dispersion consisting of the EudragitV RS 30D with dibutyl phthalate as plasticizer with other excipients as stated in Table 2 (Coat 1). The second set of drug base pellets is coated as Pellet type – D, Pellet type – E and Pellet type – F with varying amount of drug release controlling polymer dispersion consisting of the EudragitV RS 30D with dibutyl sebacate as plasticizer with other excipients as stated in Table 2 (Coat 1). All pellets are then applied with enteric coating dispersion consisting of methacrylic acid copolymer dispersion and triethyl citrate as plasticizer with the composition as described in Table 3 (Coat 2). The drug release rate controlling dispersion is mixed for 30–45 min using Lightnin mixer fitted with T-bar propeller assembly (SPX Flow Technology, Mt. Read Blvd., Rochester, NY). The enteric coating solution is also prepared using Lightnin mixer and the solution is mixed for 60 min. The diltiazem hydrochloride pellets are loaded into the Glatt Fluid Bed Process fitted with 3200 Wurster column bowl (Glatt Air Techniques Inc., Spear Road, Ramsey, NJ) and warmed to bed temperature of 35–40 C. The pre-warmed drug base pellets are coated with coating solution for Coat 1 comprising of the EudragitV RS 30D dispersion solution according to type of pellet in the coating. The coating is performed at by maintaining the product temperature between R
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28 C and 35 C. After the Coat 1 solution is sprayed, the spray system is purged with purified water for 10 min while the pellets are fluidized in the fluid bed processor. Once the purging is completed the Coat 2, enteric coating solution is sprayed by maintaining the product temperature between 28 C and 35 C. The parameters maintained for the fluid bed process Wurster system coating are presented in Table 4. The final coated pellets are dried in the fluid bed processor for 15 min. The coating parameters for the Coat 1 and Coat 2 were maintained for each type of pellet coating (Type A, B, C, D, E, and F). The coated pellets of Type A, B, and C containing dibutyl phthalate plasticizer and pellets of Type D, E, and F contain dibutyl sebacate as plasticizer are sampled individually, to perform the drug release dissolution profile evaluation. The final dosage form of diltiazem hydrochloride containing 300 was prepared by mixing the Type A, Type B, and Type C pellets in a ratio of 1:1:3 in a bin (Inox Industries Inc., Brampton, ON, Canada). The blend of coated pellets are mixed by tumbling the bin using bin tumbler (GEA Process Engineering Ltd., Eastleigh, Hampshire, UK) for 10 min at 10 rpm. Similarly the coated pellets of Type D, Type E, and Type F are also sampled individually for dissolution profile evaluation and then mixed in the ratio of 1:1:3 for 300 mg final dosage forms. The mixed coated pellets are filled in empty gelatin capsules containing pellets equivalent to 300 mg of diltiazem hydrochloride using IMA Impressa 130 capsule filling machine (IMA North America Inc., New Lancaster Road, Leominster, MA). Drug release studies Coated drug pellets of Type A, B, and C containing dibutyl phthalate as plasticizer and Type D, E, and F contain dibutyl sebacate were evaluated for drug release properties in 900 ml of 0.1 N hydrochloric Table 3. Composition of aqueous polymeric coating of methacrylic acid copolymer dispersion for Coat 2 enteric coating for the pellets Type A, B, C, D, E, and F. Ingredient Methacrylic acid copolymer dispersiona Triethyl citrate Purified water a
Table 1. Typical processing parameters for the VG100 wet granulator (Glatt Air Techniques Inc.) for diltiazem hydrochloride base pellets. Manufacturing stage Dry mixing Granulating solution addition
Wet mixing Drying
Parameters
Set points/Ranges
Impeller speed (rpm) Chopper speed (rpm) Impeller speed (rpm) Chopper speed (rpm) Spray rate (g/min) Nozzle size Spray angle ( ) Impeller speed (rpm) Chopper speed (rpm) Inlet air temperature ( C) Air flow (SCFM)
60 1000 35–55 500–1000 4000 SS-5 (full cone) 65 35–55 500–1000 60 2000
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(% w/w) 49.0 2.0 49.0
30% dispersion.
Table 4. Typical processing parameters for the fluid bed process (Glatt Air Techniques Inc.) for coating diltiazem hydrochloride base pellets for EudragitV RS30D polymer dispersion coating for Coat 1 and methacrylic acid copolymer dispersion for Coat 2. R
Parameters Product temperature ( C) Process air temperature ( C) Spray rate (g/min) Atomization air pressure (psi) Inlet air flow (cfm) Wurster column height (mm) Curing at 40 C (min)
Coat 1
Coat 2
28–35 28–35 400–1500 28–44 2400–3000 30–60 30–90
28–35 28–35 300–1000 28–44 2400–3000 30–60 30–90
Table 2. Composition of aqueous polymeric coating of EudragitV RS30D for Coat 1 used for the rate controlling film coating for pellets Type A, B, C, D, E, and F. R
Ingredient EudragitV RS 30D Dispersiona Dibutyl phthalate Dibutyl sebacate Polysorbate 80 Talc Purified water R
a
30% dispersion.
Type–A (% w/w) 33.6 3.5 – 0.2 11.2 51.5
Type–B (% w/w) 35.2 4.3 – 0.2 10.0 50.3
Type–C (% w/w) 34.5 3.2 – 0.2 11.3 50.8
Type–D (% w/w) 33.6 – 3.5 0.2 11.2 51.5
Type–E (% w/w) 35.2 – 4.3 0.2 10.0 50.3
Type–F (% w/w) 34.5 – 3.2 0.2 11.3 50.8
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acid solution using USP 40 dissolution apparatus # 2 in a fully automated Distek water bath dissolution instrument, model 2500 (Distek Inc., New Brunswick, NJ) equipped with HP8909 2A multichannel pump (Agilent Technologies Canada Inc., Mississauga, ON, Canada). For testing of each pellet type, an amount of pellets equivalent to 300 mg of diltiazem hydrochloride is placed in each of the vessel and agitated at 100 rpm. The water bath temperature is maintained at 37 ± 0.5 C. The absorbance is measured at 238 nm on HP Chemstation UV–Visible spectrometer controlled by HP Chemstation dissolution software (Agilent Technologies Canada Inc., Mississauga, ON, Canada). The samples are withdrawn automatically at the interval of 3, 6, and 12 h for Type A and D pellets, 6, 12, 18, 24, and 30 h for Type B, C, E and F pellets. The dissolution test is also conducted on the final blended pellets comprising of Type A, B, and C for dibutyl phthalate plasticizer evaluation and blended pellets comprising of Type D, E, and F for dibutyl sebacate plasticizer using USP 40 dissolution apparatus # 2 in a fully automated Distek water bath dissolution instrument, model 2500 (Distek Inc., New Brunswick, NJ) equipped with HP8909 2A multi-channel pump (Agilent Technologies Canada Inc., Mississauga, ON, Canada). Place one capsule in each vessel and agitated at 100 rpm. The water bath temperature is maintained at 37 ± 0.5 C. The absorbance is measured at 238 nm on HP Chemstation UV–Visible spectrometer controlled by HP Chemstation dissolution software (Agilent Technologies Canada Inc., Mississauga, ON, Canada). The samples are withdrawn automatically at the interval of 6, 12, 18, 24, and 30 h.
Results and discussion The plasticizer in the polymeric film dispersion has greater influence on reducing the glass transition temperature as a function of the molecular mobility of polymer chain. One of the process to achieve extended release of the active ingredient is the use of diffusion controlled polymeric film coating. Multi-particulate dosage form such as pellets in capsules are more complex to manufacture, but are considered more reliable in terms of their biopharmaceutical behavior. These multi-particulate systems act like small diffusion cells and the undissolved active drug is released at a constant rate depending on the diffusion controlling polymer film. The EudragitV RS 30D polymeric film is considered slightly permeable and the film formed with this polymer swells in contact with aqueous medium independent of pH of the medium. The EudragitV RS 30D polymer has a glass transition temperature of 58 C and addition of suitable plasticizer is required to ensure proper film formation with sufficient film flexibility. The choice of dibutyl sebacate to replace the dibutyl phthalate as plasticizer for the product developed with a proven bioequivalence is based on the properties of the dibutyl sebacate as it is widely used in the pharmaceutical formulations for polymeric coatings. Dibutyl sebacate has a solubility of 40 mg/l at 20 C, it is odorless and colorless with a very favorable thermal characteristics, as it remains in liquid state up to 10 C with a very high boiling point of 344 C. Dibutyl sebacate remains within the polymeric system upon exposure to coating system during drug release which makes it more suitable candidate for study (Snejdrova and Dittrich 2012). The objective of the study was to evaluate the impact of substituting dibutyl phthalate from an existing and established polymer coating system with proven stability evaluation of product shelf life with another plasticizer dibutyl sebacate with no impact to product. The use of hydrophobic dibutyl phthalate (20% w/w, on dry polymer basis) provides sufficient flexibility and minimum film forming temperature (MFT) less than 35 C. The minimum film forming temperature with the use of dibutyl phthalate in the R
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concentration of 10% is around 24 C and with 20% it drops to 10 C (Lehmann 1989). The permeability of the polymer file formed by EudragitV RS 30D is influenced by the type of plasticizer added to the coating dispersion. The addition of dibutyl phthalate to the coating dispersion show the lowest permeability of 5.4 mg/cm2 h with a solubility of 0.04% in water at room temperature (Lehmann 1986). The use of dibutyl phthalate as plasticizer in pharmaceutical polymeric film coating was classical and variably used (Siepmaan et al. 2006). The studies conducted on the developmental and reproductive toxicity suggested to substitute the dibutyl phthalate in polymeric film coating dispersions with suitable plasticizer without compromising on the properties and making change in the film coating systems. The study conducted to substitute plasticizer dibutyl sebacate is evaluated which is recommended plasticizer for the EudragitV RS 30D and provides similar plasticization as dibutyl phthalate on the glass transition temperature and minimum film forming temperature. The dibutyl sebacate has a solubility in water around 40 mg/L at 20 C, and it is odorless and colorless. It exhibits characteristic thermal behavior above 10 C as it remains as a liquid with a boiling point of 344 C. The toxicological data available classify it as non-toxic after oral administration and also considered non-irritating on dermal contact (Snejdrova and Dittrich 2012). The coating solution preparation for Coat 1 containing EudragitV RS 30D polymer dispersion with dibutyl phthalate and dibutyl sebacate is similar and has no impact in the dispersion solution preparation. The coated pellets with Coat 1 polymer containing dibutyl phthalate as plasticizer and finally coated with Coat 2 polymer solution for Type A, B, and C were compared with Type D, E, and F coated with Coat 1 polymer solution containing dibutyl sebacate and finally coated with Coat 2 polymer solution with respect to drug release profile. The dissolution profiles for Type A and D (Figure 1), Type B and E (Figure 2), and Type C and F (Figure 3) are comparable and show no difference in the drug release profile. This indicates that the replacement of the dibutyl phthalate with dibutyl sebacate as plasticizer show no difference in the performance in controlling the drug release from the drug pallets coated with permeable rate controlling polymer. The three types of pellets coated as Type A, B, and C with dibutyl phthalate as plasticizer and pellets coated as Type D, E, and F contain dibutyl sebacate as plasticizer were mixed to make two types of blends to fill in empty gelatin capsules. The two R
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Figure 1. Comparative drug release profile of pellets A, coated with EudragitV RS30D containing dibutyl phthalate as plasticizer and pellets D, coated with EudragitV RS30D containing dibutyl sebacate as plasticizer in 0.1 N hydrochloric acid dissolution medium. R
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PHARMACEUTICAL DEVELOPMENT AND TECHNOLOGY
Figure 2. Comparative drug release profile of pellets B, coated with EudragitV RS30D containing dibutyl phthalate as plasticizer and pellets E, coated with EudragitV RS30D containing dibutyl sebacate as plasticizer in 0.1 N hydrochloric acid dissolution medium. R
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Figure 3. Comparative drug release profile of pellets C, coated with EudragitV RS30D containing dibutyl phthalate as plasticizer and pellets F, coated with EudragitV RS30D containing dibutyl sebacate as plasticizer in 0.1 N hydrochloric acid dissolution medium.
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Figure 4. Comparative drug release profile of Diltiazem CD Capsules 300 mg, coated with EudragitV RS30D containing dibutyl phthalate as plasticizer and Diltiazem CD Capsules 300 mg, coated with EudragitV RS30D containing dibutyl sebacate as plasticizer in 0.1 N hydrochloric acid dissolution medium of pH 1.2. R
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types of final capsules containing pellets equivalent to 300 mg of diltiazem hydrochloride were again evaluated for drug release profile for the period of 30 h in in vitro conditions. The dissolution profiles obtained from the product coated with rate controlling polymer with dibutyl phthalate plasticizer and product coated with rate controlling polymer with dibutyl sebacate plasticizer in 0.1 N hydrochloric acid dissolution medium of pH 1.2 are similar (Figure 4). The capsule dosage form containing diltiazem hydrochloride pellets equivalent to 300 mg are further tested in the phosphate buffer dissolution medium of pH at 4.4 and 6.3 and the dissolution profiles are comparable (Figures 5 and 6). There is no impact observed on the drug release characteristics with the two plasticizers in changing dissolution medium pH ranges. The final in vitro dissolution performance indicate that the replacement of the dibutyl phthalate plasticizers from the rate controlling polymer dispersion with dibutyl sebacate has no impact on the polymerization of the polymers on the substrate surface. There is no impact of dissolution medium pH change as the rate controlling polymer is not impacted by changes in pH of the medium. There is no difference in the product in vitro drug release observed after changing the plasticizer to dibutyl sebacate.
Figure 5. Comparative drug release profile of Diltiazem CD Capsules 300 mg, coated with EudragitV RS30D containing dibutyl phthalate as plasticizer and Diltiazem CD Capsules 300 mg, coated with EudragitV RS30D containing dibutyl sebacate as plasticizer in phosphate buffer dissolution medium of pH 4.4. R
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Figure 6. Comparative drug release profile of Diltiazem CD Capsules 300 mg, coated with EudragitV RS30D containing dibutyl phthalate as plasticizer and Diltiazem CD Capsules 300 mg, coated with EudragitV RS30D containing dibutyl sebacate as plasticizer in phosphate buffer dissolution medium of pH 6.3. R
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Figure 7. Comparative drug release profile of Diltiazem CD Capsules 300 mg, coated with EudragitV RS30D containing dibutyl sebacate as plasticizer in 0.1 N hydrochloric acid dissolution medium of pH 1.2, at time 0, 3, 6, and 9 months stored at room temperature condition of 25 C ± 2 C/60% ± 5% RH. R
To investigate the influence of storage temperature on the drug release rate, the capsules containing the pellets coated with EudragitV RS 30D dispersion polymer containing dibutyl sebacate were stored on stressed condition. The capsules packaged in HDPE bottles were kept at controlled room temperature of 25 C ± 2 C/60% RH ±5% RH, accelerated condition of 40 C ± 2 C/75% RH ±5% RH, and intermediate condition of 30 C ± 2 C/65% RH ±5% RH (FDA 2003). The samples were withdrawn from storage conditions for dissolution profile evaluation at the interval of time 3, 6, and 9 months for room temperature, 3 and 6 months at accelerated temperature conditions and 6 and 9 months at intermediate conditions. The dissolution profiles obtained from each evaluation are plotted as mean on 6 units tested. The room temperature samples show no change in the performance of rate controlling polymer on aging (Figure 7). The accelerated condition (Figure 8) and intermediate condition samples (Figure 9) show no difference in the dissolution profile indicating that the use of dibutyl sebacate as plasticizer in the coat 1 coating has no impact on the product performance in in vitro dissolution. The film coating with EudragitV RS 30D dispersion containing dibutyl sebacate as plasticizer is equilibrated and has no aging effect. The aging effect is normally observed and depends on the coating formulation, coating conditions, and curing conditions (Wu and McGinity 2001; Amighi and Moes 1996). Many researchers have reported pellets coated with EudragitV RS 30D dispersion should not be exposed to temperature above the softening temperature of the film, as it could cause changes to the drug release performance (Bodmeier et al. 1997). The glass transition temperature (Tg) for EudragitV RS 30D with approximately 35% of dibutyl sebacate is around 35–40 C. The final drying process for coated tablet is performed at temperature of 40 C, was found to be satisfactory to ensure the complete fusion of latex nanoparticles and removal of residual moisture from the film coating with no aging effect on storage at room temperature. The presence of dibutyl sebacate is allowing the complete coalescence of the latex nanoparticles to form a smooth, continuous film to control the drug release profile.
Figure 8. Comparative drug release profile of Diltiazem CD Capsules 300 mg, coated with EudragitV RS30D containing dibutyl sebacate as plasticizer in 0.1 N hydrochloric acid dissolution medium of pH 1.2, at time 0, 3, and 6 months stored at accelerated temperature condition of 40 C ± 2 C/75% ± 5% RH. R
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Figure 9. Comparative drug release profile of Diltiazem CD Capsules 300 mg, coated with EudragitV RS30D containing dibutyl sebacate as plasticizer in 0.1 N hydrochloric acid dissolution medium of pH 1.2, at time 0, 6, and 9 months stored at intermediate temperature condition of 30 C ± 2 C/65% ± 5% RH. R
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a rate controlling film coating is not impacted by use of dibutyl sebacate in the equivalent quantity in the coating formulation. The dissolution profiles obtained for the three types of coated pellet are similar when coated with coating solution containing dibutyl phthalate as plasticizer and when coated with coating solution containing dibutyl sebacate. The porosity of the polymeric film formed by the EudragitV RS 30D is not altered by substitution of plasticizer. The use of dibutyl sebacate in coating formulation provided the similar effect in lowering the glass transition temperature and minimum film forming temperature for the EudragitV RS 30D and the drug release profile is not influenced by the change. The study also demonstrated that there is no aging effect on the coated pellets as the polymer is completely cured during the manufacturing cycle before encapsulation process. The aging influence is studied at elevated temperature and humidity for sufficient time to ensure no influence on the drug release performance. R
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Conclusions The current study demonstrated that the substitution of dibutyl phthalate as plasticizer with EudragitV RS 30D dispersion to form R
Disclosure statement No potential conflict of interest was reported by the authors.
PHARMACEUTICAL DEVELOPMENT AND TECHNOLOGY
ORCID Rakesh Singh Chaudhary
http://orcid.org/0000-0002-0628-6850
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