International Journal of Biological Macromolecules 67 (2014) 295–302
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Effect of plasticizer on drug crystallinity of hydroxypropyl methylcellulose matrix film Brajabihari Panda, Aditi Singh Parihar, Subrata Mallick ∗ Department of Pharmaceutics and Pharmaceutical Technology, School of Pharmaceutical Sciences, Siksha ‘O’ Anusandhan University, Kalinganagar, Ghatikia, Bhubaneswar 751003, Orissa, India
a r t i c l e
i n f o
Article history: Received 18 January 2014 Received in revised form 9 March 2014 Accepted 19 March 2014 Available online 28 March 2014 Keywords: Hydrophilic plasticizer Matrix film Telmisartan
a b s t r a c t Effect of different hydrophilic plasticizers on drug crystallinity of hydroxypropyl methylcellulose (HPMC) matrix film was studied. HPMC films containing telmisartan using different plasticizers were prepared by casting method. Drug crystallinity in the films was examined using polarized light microscopy (PLM), scanning electron microscopy (SEM), and x-ray diffractometry (XRD) to describe their phase behavior/solid state miscibility/crystal growth and drug–polymer–plasticizer interaction. HPMC and plasticizer were compatible with the drug and no phase separation was observed upon solvent evaporation. Plasticized-HPMC contributed a major role in the significant inhibition of crystal growth of the drug in the film. The triethanolamine film produced a relatively smooth surface in comparison to the other films in the submicron level. The films have not shown any significant changes even after exposure to stress (40◦ C/75% RH, 6 w). Triethanolamine as plasticizer brought about amorphization of telmisartan to the maximum extent in the film which is technologically more advantageous than the others owing to its anticipated better bioavailability. © 2014 Elsevier B.V. All rights reserved.
1. Introduction Cellulose ethers, the hydrophilic polymers derived from cellulose have been used since long time in pharmaceutical industries. Moreover, they exhibit appropriate biological properties which make them suitable for biomedical applications [1]. Hydroxypropyl methylcellulose (HPMC), a cellulose derivative polymer, is used in the preparation of many film type drug delivery systems [2,3] and also other biomaterial matrices [4,5]. Plasticizers play a very important role in the formulation of film type drug delivery systems. Without a plasticizer, a very hard and brittle type film is produced. Plasticizers used in the film formulation are selected mainly according to the biocompatibility, plasticizer–polymer–drug compatibility, drug release and flexibility [6–9]. The workability and flexibility of the polymer are improved by increasing the intermolecular separation of the polymer molecules after loosening of tightness of intermolecular forces upon incorporation of plasticizer [10–14] and this results in an improvement of patient compliance. The lubrication theory describes that plasticizers act as internal lubricants by reducing frictional forces between polymer chains. As per gel theory plasticizers play role in breaking
∗ Corresponding author. Tel.: +91 674 2386209; fax: +91 674 2386271. E-mail addresses: s [email protected], [email protected] (S. Mallick). http://dx.doi.org/10.1016/j.ijbiomac.2014.03.033 0141-8130/© 2014 Elsevier B.V. All rights reserved.
polymer–polymer interactions (e.g., hydrogen bonds and van der Waals or ionic forces). The aggregation process caused by the intermolecular attraction of the polymer is reduced after the incorporation of the plasticizer and it can also cause in an increase in bioadhesiveness. Gal and Nussinovitch [15] have reported that inclusion of plasticizer in the transdermal patches exhibited an additional skin bioadhesion. Polyethylene glycols and triethanolamine showed high plasticizing effect [16]. Lin et al. [6,17] have examined that addition of polyethylene glycol 200 or propylene glycol as a secondary plasticizer improved flexibility, adhesive properties and transparency of the film. Polyethylene glycols are highly biocompatible and their miscibility decreases with molecular mass [18]. PEG very effectively plasticized in a 30% concentration of poly(lactic acid) but above 50% it caused an increasing crystallinity of PEG, resulting in an increase in modulus and a corresponding decrease in elongation at break [19]. PEG 400 was proved to be a more effective plasticizer [20] than PEG1000 for HPMC films [21–23]. Dimethyl sulfoxide (low toxic potential) is included in the selection list of plasticizers also appropriate for dosage forms in the 35th edition of the United States Pharmacopoeia. In the present study, HPMC films plasticized with propylene glycol (PG), polyethylene glycol 400 (PEG), dimethyl sulfoxide (DMSO) or triethanolamine (TEA) were produced incorporating a model antihypertensive drug, telmisartan. How the crystallinity of telmisartan in the HPMC matrix has been influenced by the plasticizer was
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Table 1 Formulation of hydroxypropyl methylcellulose films containing telmisartan, plasticized with different hydrophilic plasticizers. Formulation
Telmisartan: Plasticizer used HPMC K15
Plasticizera (%)
Casting solvent
Tpg10 Tpg30 Tpeg30 Tdmso30 Ttea30
1:3 1:3 1:3 1:3 1:3
10 30 30 30 30
Water and ethanol Water and ethanol Water and ethanol Water and ethanol Water and ethanol
a
PG PG PEG DMSO TEA
Plasticizer as percentage of polymer weight.
the objective of the study. Extensive literature survey revealed that this type of study has not been performed earlier. All plasticizers chosen were hydrophilic substances containing hydroxyl or amino functions. The prepared films were analyzed using scanning electron microscopy (SEM), polarized light microscopy (PLM), and x-ray diffractometry (XRD) to describe their phase behavior/solid state miscibility/crystal growth and drug–polymer–plasticizer interaction. Moreover, physical stability of the films was performed by analyzing after exposure at 40◦ C/75% RH for 6 weeks. A mechanistic explanation on the evolution of unique physical structures in the films prepared from a variety of plasticizers was postulated based on the observed results.
in desiccators at ambient temperature for 24 h were taken out and placed in desiccator containing 100 ml of supersaturated solution of potassium chloride, sodium chloride and aluminium chloride to maintain 84%,74% and 79% relative humidity respectively until a constant weight for the film was obtained. The percentage of moisture uptake was calculated as the difference between final and initial weight with respect to initial weight and a mean of four determinations was recorded for each film. 2.3. Polarized light microscopy Polarized light microscopy was performed with an Olympus MLX polarizing optical microscope. Samples of telmisartan pure drug crystals and films were spread over a glass slide and covered with another slide. The specimens were visualized for the presence of birefringence under polarized light and pictured using a digital camera (Olympus Imaging Corp, Model: E-520, Software: Version 1.1). All images were taken at room temperature with an exposure time of 0.2 s. 2.4. Scanning electron microscopy
2. Experimental
The surface morphology of the films was visualized by a Scanning electron microscope (JSM- 6390, JEOL, Tokyo, Japan). The dried samples were sputtered with gold and scanned at room temperature using an accelerated voltage of 5/15 kV.
2.1. Fabrication of films
2.5. X-ray diffractometry
Matrix films of hydroxypropyl methylcellulose K15M (Biodeals Pharma Ltd, India) as hydrophilic polymer containing telmisartan were prepared by casting and solvent evaporation technique [24,25] using different plasticizers such as propylene glycol, polyethylene glycol 400, triethanolamine (all of Merck, Mumbai, India) and dimethyl sulfoxide (Burgoyne, Mumbai, India)). HPMC was soaked in cold distilled water and left overnight for complete swelling. Separately, telmisartan (Biodeals Pharma Ltd, India) was dissolved in ethanol (same volume as of water used in HPMC soaking) followed by the addition of plasticizer with continuous stirring (Magnetic stirrer, REMI 1MLH, India). Drug solution was poured on the swelled polymer and a uniform dispersion was prepared with constant magnetic stirring for 12 h. Casting of the final dispersion was then done in a flat bottomed petridish and dried at 40◦ C for 48 h or more for complete drying. The dried films were preserved in an air tight container in a cool dark place until use. The composition of the polymeric films has been tabulated in Table 1.
The x-ray diffraction patterns of pure telmisartan (as available) and the films were recorded using x-ray diffractometer (Model: Philips analytical X-Ray with PC-APD, Diffraction Software). The voltage and current were 40 kv and 15 mA, respectively. Anode ˚ was used as a source of Material Cu, K-Alpha (radiation 1.5406 A) x-rays. Measurements were undertaken at a scan speed of 1◦/min for the scanning angle ranging from 10◦ to 70◦ . 2.6. Differential scanning calorimetry
2.2. Evaluation of physical characteristics of the films
2.7. In-vitro dissolution
Individually prepared films were accurately weighed and placed in a desiccator containing activated silica at laboratory ambient temperature until two successive weights found constant. Percent moisture content was evaluated as a difference between initial and final weight with respect to final weight [8]. The thickness of the films was measured at six different places of each formulated film using digital micrometer (Mitutoyo, Japan). Folding endurance was determined by repeatedly folding a strip of film at the same place until it broke or 200 times which is considered satisfactory to reveal good film properties [26]. For determination of surface pH of each film Bottenberg et al. method was adopted [27]. A small strip of each film was allowed to swell by keeping it in contact with 1 ml of distilled water (pH 6.5 ± 0.5) for 2 h at laboratory ambient temperature, and the pH was recorded by bringing the electrode into contact with the surface of the film and allowing it to equilibrate for 1 min. A mean of four readings was noted for each formulation. For moisture uptake determination accurately weighed films kept
USP XXIV dissolution apparatus (Electrolab, dissolution tester USP, TDT06L, India) rotating paddle method was used to study drug release from the films. A small strip of each film was accurately weighed and attached to the glass slide with an adhesive (cyanoacrylate) and placed inside bottom of the dissolution vessel. After 2 min, the vessel was filled with 1000 ml of phosphate buffer (pH 7.4) and maintained at 37.0 ± 0.5 ◦ C while stirring at 50 rpm and dissolution continued. At specified intervals of time, samples were withdrawn through 0.45 membrane filter and analyzed spectrophotometrically and reported as an average of three measurements.
Pure telmisartan and films were subjected to thermal analysis by differential scanning calorimetry (DSC Q10 V9.4 Build 287) to examine possible interactions between drug and excipients. Samples were weighed into the DSC pan, and the sealed pan was placed in the sample side of the instrument. Scans were carried out at a rate of 10 ◦ C/min at temperatures of between 30 ◦ C and 330 ◦ C, using a nitrogen gas purge at 50 ml/min.
2.8. Stability of the films Films were placed in open petridish and exposed at 40 ◦ C/75% RH in a humidity cabinet (Temperature Cum Humidity Controller, Thermotech, TH-7004, Model: IK-116, IKON Instrument, India).
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Table 2 Physicochemical properties of plasticized hydroxypropyl methylcellulose film. Formulation
Tpg10 Tpg30 Tpeg30 Tdmso30 Ttea30 a
Thickness (mean ± sd; n = 6) (mm)
0.209 ± 0.012 0.232 ± 0.013 0.241 ± 0.015 0.215 ± 0.018 0.218 ± 0.017
Weighta (mean ± sd; n = 6) (mg)
44.5 ± 0.91 48.7 ± 0.67 52.3 ± 0.69 44.9 ± 0.87 41.6 ± 0.59
Folding endurance
>200 >200 >200 >200 >200
Surface pHa (mean ± sd; n = 4)
7.10 ± 0.08 7.43 ± 0.04 7.32 ± 0.04 7.37 ± 0.09 7.40 ± 0.07
% Moisture uptake (mean ± sd, n = 4)
% Moisture content (mean ± sd; n = 4)
RH 74%
RH 79%
RH 84%
2.84 ± 0.07 3.52 ± 0.29 3.83 ± 0.01 4.16 ± 0.06 4.86 ± 0.09
4.63 ± 0.40 5.07 ± 0.27 5.56 ± 0.26 7.56 ± 0.57 8.04 ± 0.12
5.51 ± 0.45 8.14 ± 0.23 9.39 ± 0.38 10.12 ± 0.46 10.79 ± 0.41
2.37 ± 0.16 2.82 ± 0.09 3.58 ± 0.09 3.89 ± 0.08 3.98 ± 0.12
Area of the film = 1.76 cm2 .
Films were examined by Scanning electron microscopy and x-ray diffractometry after the exposure of 6 weeks. 3. Results and discussion During preparation of drug–polymer dispersion a sufficient time under magnetic stirring was allowed for uptake of the plasticizer by the polymer (in the form of a viscous liquid) for formation of a homogeneous plasticized system [28]. Ideal plasticizers should be miscible and compatible in all proportions with plastic components [29]. In drug–polymer liquid polymer atoms were arranged in a random way similar to the disorder we find in a liquid solution and the incorporated plasticizer in this amorphous phase of polymer, modified its amorphous halo [30]. The thin films were easily removed from the cast plate and the film morphology was described by scanning electron microscopy and polarized light microscopy for the phase behavior, solid state miscibility and/or crystal growth of the drug in the polymer matrix in submicron level in the following sections. X-ray diffractometry studies were described to evident any trace of crystallinity of the drug in the film. 3.1. Physical characterization of the films Results of physicochemical properties of the plasticized hydroxypropyl methylcellulose films have been summarized in Table 2. The thickness and weight of all the film samples were found uniform within each formulation and varied between 0.209 and 0.242 mm in thickness and 41.6 to 52.3 mg (1.76 cm2 ) respectively. All film formulations were translucent and colourless exhibited good folding endurance exceeding 200, indicating that they were tough and flexible and not brittle. The surface pH of the films ranged from 7.10 to 7.43 and hence no mucosal irritation was expected [31] and the films could be utilized as transmucosal drug delivery system. The moisture uptake of the films was monitored at different ambient relative humidity (RH) values of 74, 79 and 84% and as expected, moisture uptake has been increased as the RH increased. Low equilibrium moisture content ranged from 2.37 to 3.98% in the films at laboratory ambient condition can protect the film from microbial contamination. Again small moisture content helps the film to remain stable without being completely dried and brittle. Ttea30 absorbed the highest moisture (moisture uptake) at all RH when compared to other films (4.86, 8.04 and 10.79% respectively). The uptake of water vapor by the film depends mainly on the chemical structure of the components of the matrix. Moisture held in the film forms hydrogen bond with the polymer chains of HPMC plasticized with soluble compound. 3.2. Film morphology In the present study, Tpg10 , Tpg30 , Tdmso30 , Tpeg30 or Ttea30 formed the polymer matrix film, whereas the drug particle was the
dispersed phase. Good dispersion of drug, effective wetting of drug particle by the polymer, and strong interfacial adhesion between two phases were required to obtain satisfactory drug delivery properties. To study the distribution and the phase size of drug crystal particle in the polymer matrix, cast film surfaces influenced by the plasticizer were examined with both of polarized light microscopy and scanning electron microscopy. Light micrographs of telmisartan drug crystals and the surface layer of the freshly prepared films have been depicted in Fig. 1a–f. Distinct crystalline structure of pure telmisartan has been observed in Fig. 1f. All the surface layers were almost relatively smooth without any significant surface porosity compared to Tpg10 (Fig. 1a). The trace amount of small drug particles spread in the polymer matrix was observed. They were lacking of definite shape, organization and distinct crystalline structure. Appearance of microparticles was very much less prominent in Tpeg30 , Tdmso30 , and Ttea30 compared to Tpg10 and Tpg30 . The structure and morphology results of all the HPMC matrix film samples showed crack-free at the submicron level of Tpg30 , Tdmso30 , Tpeg30 and Ttea30 (SEM photomicrographs in Fig. 2a–h). The Tpeg30 film (Fig. 2c and d) displayed a relatively smooth surface, whereas the films Tpg30 , Tdmso30 and Ttea30 were rougher (Fig. 2 a, b, e, f, g, and h). As displayed in the figure (Fig. 2 a, b, e, and f) the drug crystallites were almost rod shaped and scattered throughout surface of the film. But the drug crystallites found in Tpeg30 and Ttea30 were almost plate shaped and scattered in the film. Most of the drug crystallites were in the fused appearance might be due to the polar surface of the cellulose fibers (HPMC) and drug. It has been suggested that the individual drug crystallites were held in the HPMC domain largely by hydrogen bonding. SEM micrograph of HPMC control film produced by Bilbao-Sáinz et al. [32] displayed a relatively smooth surface rather than the matrix in the MCC-reinforced nanocomposite films. The morphology of the HPMC control film (without any plasticizer) prepared from an aqueous solution analyzed by SEM exhibited a high degree of porosity evenly distributed throughout the film [33]. The results of the present study indicated that with the addition of plasticizers (containing hydroxyl or amino functions) has further influenced the decrease of crystallinity of the drug, and an increase in the flexibility of the films might be owing to the decrease in the number of weak inter- and intramolecular hydrogen bonds of the base polymer HPMC and drug.
3.3. X-ray diffraction studies X-ray diffraction pattern of pure telmisartan and formulated freshly prepared films has been displayed in Fig. 3. The pattern of pure drug exhibited high intensity reflections with characteristic peaks at 10.87◦ , 18.20◦ , 26.37◦ , 42.25◦ , 48.38◦ and 68.75◦ (2Â) in the angle range of 10–70◦ (2Â). The pattern of physical mixture of drug and polymer (Tpm, 1:3) did not present any significant difference compared to crystalline telmisartan (slightly poor in reflections of 2Â at 10.86◦ , 18.22◦ , 26.25◦ , 42.25◦ , 48.37◦ and 68.76◦ ).
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Fig. 1. Polarized light micrographs of telmisartan pure drug crystals and films prepared using different plasticizers in HPMC matrix (a) Tpg10 ; (b) Tpg30 ; (c) Tpeg30 ; (d) Tdmso30 ; (e) Ttea30 ; and (f) Tel. All magnifications at 400× with an exposure time of 0.2 s.
The XRD pattern of the films containing different plasticizer has shown significantly reduced reflections of the drug due to presence of hydroxypropyl methylcellulose in all the films in the same drug–polymer ratio (1:3). The status of the polymer (HPMC) in the film was in the amorphous phase. Parameswara et al. [34] also found very poor intensity reflections in the XRD pattern of the polymer upon addition of PEG as plasticizer in HPMC films (without drug). Bragg peaks appeared on the top of an amorphous halo in the diffractograms of the film samples. X-rays were scattered in many directions leading to a large bump distributed in a wide range (2Â) instead of high intensity narrower peaks. Tpg10 and Tpg30 films have presented almost same pattern (2Â: shouldering at 24.0◦ and some moderate reflections at 42.12, 48.37 and 68.81◦ ). The peaks intensity of Tpeg30 (2Â: shouldering at 26.45◦ and some reflections at 42.13, 48.36 and 68.75◦ ) were comparatively less than Tdmso30 (2Â: shouldering at 24.1◦ and the reflections at 42.25, 48.37 and 68.74◦ ). DMSO does not contain hydrogen bond donor functionality and easily can form solvent cavities to accommodate a drug in DMSO than in water. The large dielectric constant of DMSO is energetically favorable to the interaction of DMSO with telmisartan that contains dipole. Telmisartan structure is asymmetric and the molecule has polarity [35]. Benzimidazole rings of telmisartan provide some enhanced hydrophobic binding.
The film formulation Ttea30 (2Â: shouldering at 25.99◦ and the reflections at 42.25, 48.38 and 68.75◦ ) showed maximum amorphization of telmisartan. Therefore, XRD results testified the reduced ordering of the crystal lattice as: The litTel > Tpm > Tpg10 > Tpg30 > Tdmso30 > Tpeg30 > Ttea30 . erature survey also revealed that the effect of polypropylene glycol used as a plasticizer on a decrease in crystallinity was lower than in PEG [36]. The steric hindrance and miscibility of the plasticizers, through their different polar functions, were the two major characteristics that could be related to the slight difference in lattice spacing of the reflections in the XRD pattern of the formulated films. Increased elongation at break (flexibility) and soft and ductile polymeric films have been produced after effectively destroying polymer crystals when the films were plasticized [37]. 3.4. Thermal analysis Fig. 4 shows the thermograms from DSC analysis of pure crystalline drug telmisartan and the film formulations. The endothermic peak observed at 269.4 ◦ C for the crystalline form corresponds with literature data regarding the melting point of Tel [38]. In the films, no endothermal peak for Tel was observed in the vicinity at 269.4 ◦ C suggesting possible molecular
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Fig. 2. Visualization of surface morphology of the fresh films by scanning electron microscope: (a) Tpg30 (magnification 500×); (b) Tpg30 (magnification 5000×); (c) Tpeg30 (magnification 500×); (d) Tpeg30 (magnification 5000×); (e) Tdmso30 (magnification 500×); (f) Tdmso30 (magnification 5000×); (g) Ttea30 (magnification 500×); (h) Ttea30 (magnification 5000×).
dispersion of Tel in polymer–plasticizer combination. Large shallow broad endothermic effects, over the temperature range 50–110 ◦ C, attributed to the removal of moisture due to the presence of HPMC in the films [39]. A small step-like behaviour at about 220 ◦ C was a manifestation of the glass transition of Tel observed in the films Tpg10 , Tpg30 , Tpeg30 and Tdmso30 . Endothermic event at around 220 ◦ C was not observed in the film, Ttea30 containing triethanolamine as plasticizer.
3.5. In-vitro dissolution studies In vitro dissolution of drug in the simulated fluid (buffered at pH 7.4 and 37 ◦ C: biologically relevant) is more important rather than the film solubility in water as a whole if it is a film type drug delivery system [26]. Plasticized-HPMC matrix system plays an important role in controlling drug dissolution from the film. In-vitro dissolution profiles of all the film formulations have been depicted in Fig. 5.
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Fig. 5. In-vitro drug dissolution profiles of plasticized-HPMC film (Tpg10 , Tpg30 , Tpeg30 , Tdmso30 and Ttea30 ).
3.6. Stability analysis of the films
Fig. 3. The XRD pattern of telmisartan crystalline drug (Tel), physical mixture of Tel and HPMC in 1:3 ratio (Tpm), and the formulated films (Tpg10 , Tpg30 , Tpeg30 , Tdmso30 , Ttea30 ).
Triethanolamine improved the drug dissolution to the great extent (98%) compared to the least by propylene glycol. The order of dissolution was observed as Tpg10 < Tpg30 < Tpeg30 < Tdmso30 < Ttea30 . Reduced crystalline intensity of Tel (poorly soluble drug) to the maximal extent in Ttea30 brought about maximum dissolution of drug and the result was also supported by XRD and thermal analysis.
Significant changes in the micrographs have not been observed after the exposure of the films at 40 ◦ C/75% RH for 6 weeks (Fig. 6a–h). All the films were crack-free at the micrometer level. The similar type of surface roughness as of freshly prepared films has not been changed severely in Tpg30 (Fig. 6a and b), Tdmso30 (Fig. 6e and f) and Ttea30 (Fig. 6g and h), whereas, Tpeg30 (Fig. 6c and d) film appeared comparatively smooth. The prominent submicron and nano-pores were much larger in Tpg30 compared to Ttea30 films. Almost rod shaped drug crystallites were consistent in Tpg30 and Tdmso30 film as observed in the fresh. The consistency of plate shaped crystallites was also noticed in Tpeg30 and Ttea30 after 6 week exposure of stressed condition of 40 ◦ C/75% RH. XRD pattern of the films after 6 weeks (40 ◦ C/75% RH) revealed no significant change in the film (data not shown) and the reduced ordering of crystallinity were: Tel (fresh) > Tpm (fresh) > Tpg10 > Tpg30 > Tdmso30 > Tpeg30 > Ttea30 . The growth of micro- and nano-crystallites of telmisartan in the films has been arrested might be due to the hydrogen bonding with the cellulose fibers of HPMC even in the favorable environment of 40 ◦ C/75% RH. Adsorption of moisture by the films (40 ◦ C/75% RH, 6 w) could not
Fig. 4. DSC thermogram of pure drug (Tel) and formulated films (Tpg10 , Tpg30 , Tpeg30 , Tdmso30 and Ttea30 ).
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Fig. 6. Surface morphology of the films by scanning electron microscope after 6 weeks of exposure at 40 ◦ C/75% RH: (a) Tpg30 (magnification 500×); (b) Tpg30 (magnification 2000×); (c) Tpeg30 (magnification 500×); (d) Tpeg30 (magnification 2000×); (e) Tdmso30 (magnification 500×); (f) Tdmso30 (magnification 2000×); (g) Ttea30 (magnification 500×); (h) Ttea30 (magnification 2000×).
bring about molecular mobility of the energetically trapped glassy phase of the drug significantly. The diffusion of small molecules (telmisartan) through the polymer matrix was very slow and could not be accelerated by water. PEG was found more suitable as chitosan plasticizer compared to PG and ethylene glycol, and the chitosan film was reported to be stable until 9 weeks of storage at ambient condition of 22 ◦ C, 40–60% RH [40].
4. Conclusions Effect of plasticizers such as propylene glycol, polyethylene glycol 400, dimethyl sulfoxide and triethanolamine on crystallinity of telmisartan in HPMC matrix films was examined using PLM, SEM, and XRD. The Tpeg30 film produced a relatively smooth surface in comparison to the other films in submicron level. Both
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water-soluble HPMC and plasticizer were compatible with the drug and did not phase separate upon solvent evaporation. PlasticizedHPMC has a major role in the significant inhibition of crystal growth of drug in the film. The good solid state miscibility of drug and polymer in the film is technologically advantageous owing to its decreased possibility to lead pore formation from polymer leaching during water immersion. Based on all the results, the increased order of amorphization of drug was observed in the film formulation as: Tpg10 < Tpg30 < Tdmso30 < Tpeg30 < Ttea30 . Relatively amorphous state of telmisartan in Ttea30 formulation in presence of triethanolamine as plasticizer is technologically more advantageous than the others owing to its anticipated better bioavailability. Although it is a thermodynamically unstable state, a physical stability study at 40 ◦ C/75% RH for 6 weeks revealed no significant change of the amorphous phase of the drug in Tpg30 , Tdmso30 , Tpeg30 and Ttea30 films. Acknowledgments The authors are very much grateful to Prof. Manoj Ranjan Nayak, President, Siksha O Anusandhan University for his encouragement and facilities. References [1] S. Bohic, P. Weiss, P. Roger, G. Daculsi, J. Mater. Sci. M 12 (2001) 201–205. [2] R. Chandak, P.R. Verma, Yakugaku Zasshi 128 (2008) 1057–1066. [3] B. Luppi, F. Bigucci, M. Baldini, A. Abruzzo, T. Cerchiara, G. Corace, et al., J. Pharm. Pharmacol. 62 (2010) 305–309. [4] Y. Amouriq, X. Bourges, P. Weiss, J. Bosco, J.M. Bouler, G. Daculsi, J. Mater. Sci. M 13 (2002) 149–154. [5] P. Weiss, P. Layrolle, L.P. Clergeau, B. Enckel, P. Pilet, Y. Amouriq, Biomaterials 28 (2007) 3295–3305. [6] S.Y. Lin, Ch.J. Lee, Y.Y. Lin, Pharmaceut. Res. 8 (1991) 1137–1143. [7] M. Rahman, Ch.S. Brazel, Prog. Polym. Sci. 29 (2004) 1223–1248. [8] P.K. De, S. Mallick, B. Mukherjee, S. Sengupta, S. Pattnaik, S. Chakraborty, Iranian J. Pharm. Res. 10 (2011) 193–201. [9] S. Pattnaik, K. Swain, A. Bindhani, S. Mallick, Drug Dev. Ind. Pharm. 37 (2011) 465–474. [10] P.V.A. Bergo, P.J.A. Sobral, Food Hydrocolloid. 21 (2007) 1285–1289.
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Contents lists available at ScienceDirect
International Journal of Biological Macromolecules journal homepage: www.elsevier.com/locate/ijbiomac
Effect of plasticizer on drug crystallinity of hydroxypropyl methylcellulose matrix film Brajabihari Panda, Aditi Singh Parihar, Subrata Mallick ∗ Department of Pharmaceutics and Pharmaceutical Technology, School of Pharmaceutical Sciences, Siksha ‘O’ Anusandhan University, Kalinganagar, Ghatikia, Bhubaneswar 751003, Orissa, India
a r t i c l e
i n f o
Article history: Received 18 January 2014 Received in revised form 9 March 2014 Accepted 19 March 2014 Available online 28 March 2014 Keywords: Hydrophilic plasticizer Matrix film Telmisartan
a b s t r a c t Effect of different hydrophilic plasticizers on drug crystallinity of hydroxypropyl methylcellulose (HPMC) matrix film was studied. HPMC films containing telmisartan using different plasticizers were prepared by casting method. Drug crystallinity in the films was examined using polarized light microscopy (PLM), scanning electron microscopy (SEM), and x-ray diffractometry (XRD) to describe their phase behavior/solid state miscibility/crystal growth and drug–polymer–plasticizer interaction. HPMC and plasticizer were compatible with the drug and no phase separation was observed upon solvent evaporation. Plasticized-HPMC contributed a major role in the significant inhibition of crystal growth of the drug in the film. The triethanolamine film produced a relatively smooth surface in comparison to the other films in the submicron level. The films have not shown any significant changes even after exposure to stress (40◦ C/75% RH, 6 w). Triethanolamine as plasticizer brought about amorphization of telmisartan to the maximum extent in the film which is technologically more advantageous than the others owing to its anticipated better bioavailability. © 2014 Elsevier B.V. All rights reserved.
1. Introduction Cellulose ethers, the hydrophilic polymers derived from cellulose have been used since long time in pharmaceutical industries. Moreover, they exhibit appropriate biological properties which make them suitable for biomedical applications [1]. Hydroxypropyl methylcellulose (HPMC), a cellulose derivative polymer, is used in the preparation of many film type drug delivery systems [2,3] and also other biomaterial matrices [4,5]. Plasticizers play a very important role in the formulation of film type drug delivery systems. Without a plasticizer, a very hard and brittle type film is produced. Plasticizers used in the film formulation are selected mainly according to the biocompatibility, plasticizer–polymer–drug compatibility, drug release and flexibility [6–9]. The workability and flexibility of the polymer are improved by increasing the intermolecular separation of the polymer molecules after loosening of tightness of intermolecular forces upon incorporation of plasticizer [10–14] and this results in an improvement of patient compliance. The lubrication theory describes that plasticizers act as internal lubricants by reducing frictional forces between polymer chains. As per gel theory plasticizers play role in breaking
∗ Corresponding author. Tel.: +91 674 2386209; fax: +91 674 2386271. E-mail addresses: s [email protected], [email protected] (S. Mallick). http://dx.doi.org/10.1016/j.ijbiomac.2014.03.033 0141-8130/© 2014 Elsevier B.V. All rights reserved.
polymer–polymer interactions (e.g., hydrogen bonds and van der Waals or ionic forces). The aggregation process caused by the intermolecular attraction of the polymer is reduced after the incorporation of the plasticizer and it can also cause in an increase in bioadhesiveness. Gal and Nussinovitch [15] have reported that inclusion of plasticizer in the transdermal patches exhibited an additional skin bioadhesion. Polyethylene glycols and triethanolamine showed high plasticizing effect [16]. Lin et al. [6,17] have examined that addition of polyethylene glycol 200 or propylene glycol as a secondary plasticizer improved flexibility, adhesive properties and transparency of the film. Polyethylene glycols are highly biocompatible and their miscibility decreases with molecular mass [18]. PEG very effectively plasticized in a 30% concentration of poly(lactic acid) but above 50% it caused an increasing crystallinity of PEG, resulting in an increase in modulus and a corresponding decrease in elongation at break [19]. PEG 400 was proved to be a more effective plasticizer [20] than PEG1000 for HPMC films [21–23]. Dimethyl sulfoxide (low toxic potential) is included in the selection list of plasticizers also appropriate for dosage forms in the 35th edition of the United States Pharmacopoeia. In the present study, HPMC films plasticized with propylene glycol (PG), polyethylene glycol 400 (PEG), dimethyl sulfoxide (DMSO) or triethanolamine (TEA) were produced incorporating a model antihypertensive drug, telmisartan. How the crystallinity of telmisartan in the HPMC matrix has been influenced by the plasticizer was
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Table 1 Formulation of hydroxypropyl methylcellulose films containing telmisartan, plasticized with different hydrophilic plasticizers. Formulation
Telmisartan: Plasticizer used HPMC K15
Plasticizera (%)
Casting solvent
Tpg10 Tpg30 Tpeg30 Tdmso30 Ttea30
1:3 1:3 1:3 1:3 1:3
10 30 30 30 30
Water and ethanol Water and ethanol Water and ethanol Water and ethanol Water and ethanol
a
PG PG PEG DMSO TEA
Plasticizer as percentage of polymer weight.
the objective of the study. Extensive literature survey revealed that this type of study has not been performed earlier. All plasticizers chosen were hydrophilic substances containing hydroxyl or amino functions. The prepared films were analyzed using scanning electron microscopy (SEM), polarized light microscopy (PLM), and x-ray diffractometry (XRD) to describe their phase behavior/solid state miscibility/crystal growth and drug–polymer–plasticizer interaction. Moreover, physical stability of the films was performed by analyzing after exposure at 40◦ C/75% RH for 6 weeks. A mechanistic explanation on the evolution of unique physical structures in the films prepared from a variety of plasticizers was postulated based on the observed results.
in desiccators at ambient temperature for 24 h were taken out and placed in desiccator containing 100 ml of supersaturated solution of potassium chloride, sodium chloride and aluminium chloride to maintain 84%,74% and 79% relative humidity respectively until a constant weight for the film was obtained. The percentage of moisture uptake was calculated as the difference between final and initial weight with respect to initial weight and a mean of four determinations was recorded for each film. 2.3. Polarized light microscopy Polarized light microscopy was performed with an Olympus MLX polarizing optical microscope. Samples of telmisartan pure drug crystals and films were spread over a glass slide and covered with another slide. The specimens were visualized for the presence of birefringence under polarized light and pictured using a digital camera (Olympus Imaging Corp, Model: E-520, Software: Version 1.1). All images were taken at room temperature with an exposure time of 0.2 s. 2.4. Scanning electron microscopy
2. Experimental
The surface morphology of the films was visualized by a Scanning electron microscope (JSM- 6390, JEOL, Tokyo, Japan). The dried samples were sputtered with gold and scanned at room temperature using an accelerated voltage of 5/15 kV.
2.1. Fabrication of films
2.5. X-ray diffractometry
Matrix films of hydroxypropyl methylcellulose K15M (Biodeals Pharma Ltd, India) as hydrophilic polymer containing telmisartan were prepared by casting and solvent evaporation technique [24,25] using different plasticizers such as propylene glycol, polyethylene glycol 400, triethanolamine (all of Merck, Mumbai, India) and dimethyl sulfoxide (Burgoyne, Mumbai, India)). HPMC was soaked in cold distilled water and left overnight for complete swelling. Separately, telmisartan (Biodeals Pharma Ltd, India) was dissolved in ethanol (same volume as of water used in HPMC soaking) followed by the addition of plasticizer with continuous stirring (Magnetic stirrer, REMI 1MLH, India). Drug solution was poured on the swelled polymer and a uniform dispersion was prepared with constant magnetic stirring for 12 h. Casting of the final dispersion was then done in a flat bottomed petridish and dried at 40◦ C for 48 h or more for complete drying. The dried films were preserved in an air tight container in a cool dark place until use. The composition of the polymeric films has been tabulated in Table 1.
The x-ray diffraction patterns of pure telmisartan (as available) and the films were recorded using x-ray diffractometer (Model: Philips analytical X-Ray with PC-APD, Diffraction Software). The voltage and current were 40 kv and 15 mA, respectively. Anode ˚ was used as a source of Material Cu, K-Alpha (radiation 1.5406 A) x-rays. Measurements were undertaken at a scan speed of 1◦/min for the scanning angle ranging from 10◦ to 70◦ . 2.6. Differential scanning calorimetry
2.2. Evaluation of physical characteristics of the films
2.7. In-vitro dissolution
Individually prepared films were accurately weighed and placed in a desiccator containing activated silica at laboratory ambient temperature until two successive weights found constant. Percent moisture content was evaluated as a difference between initial and final weight with respect to final weight [8]. The thickness of the films was measured at six different places of each formulated film using digital micrometer (Mitutoyo, Japan). Folding endurance was determined by repeatedly folding a strip of film at the same place until it broke or 200 times which is considered satisfactory to reveal good film properties [26]. For determination of surface pH of each film Bottenberg et al. method was adopted [27]. A small strip of each film was allowed to swell by keeping it in contact with 1 ml of distilled water (pH 6.5 ± 0.5) for 2 h at laboratory ambient temperature, and the pH was recorded by bringing the electrode into contact with the surface of the film and allowing it to equilibrate for 1 min. A mean of four readings was noted for each formulation. For moisture uptake determination accurately weighed films kept
USP XXIV dissolution apparatus (Electrolab, dissolution tester USP, TDT06L, India) rotating paddle method was used to study drug release from the films. A small strip of each film was accurately weighed and attached to the glass slide with an adhesive (cyanoacrylate) and placed inside bottom of the dissolution vessel. After 2 min, the vessel was filled with 1000 ml of phosphate buffer (pH 7.4) and maintained at 37.0 ± 0.5 ◦ C while stirring at 50 rpm and dissolution continued. At specified intervals of time, samples were withdrawn through 0.45 membrane filter and analyzed spectrophotometrically and reported as an average of three measurements.
Pure telmisartan and films were subjected to thermal analysis by differential scanning calorimetry (DSC Q10 V9.4 Build 287) to examine possible interactions between drug and excipients. Samples were weighed into the DSC pan, and the sealed pan was placed in the sample side of the instrument. Scans were carried out at a rate of 10 ◦ C/min at temperatures of between 30 ◦ C and 330 ◦ C, using a nitrogen gas purge at 50 ml/min.
2.8. Stability of the films Films were placed in open petridish and exposed at 40 ◦ C/75% RH in a humidity cabinet (Temperature Cum Humidity Controller, Thermotech, TH-7004, Model: IK-116, IKON Instrument, India).
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Table 2 Physicochemical properties of plasticized hydroxypropyl methylcellulose film. Formulation
Tpg10 Tpg30 Tpeg30 Tdmso30 Ttea30 a
Thickness (mean ± sd; n = 6) (mm)
0.209 ± 0.012 0.232 ± 0.013 0.241 ± 0.015 0.215 ± 0.018 0.218 ± 0.017
Weighta (mean ± sd; n = 6) (mg)
44.5 ± 0.91 48.7 ± 0.67 52.3 ± 0.69 44.9 ± 0.87 41.6 ± 0.59
Folding endurance
>200 >200 >200 >200 >200
Surface pHa (mean ± sd; n = 4)
7.10 ± 0.08 7.43 ± 0.04 7.32 ± 0.04 7.37 ± 0.09 7.40 ± 0.07
% Moisture uptake (mean ± sd, n = 4)
% Moisture content (mean ± sd; n = 4)
RH 74%
RH 79%
RH 84%
2.84 ± 0.07 3.52 ± 0.29 3.83 ± 0.01 4.16 ± 0.06 4.86 ± 0.09
4.63 ± 0.40 5.07 ± 0.27 5.56 ± 0.26 7.56 ± 0.57 8.04 ± 0.12
5.51 ± 0.45 8.14 ± 0.23 9.39 ± 0.38 10.12 ± 0.46 10.79 ± 0.41
2.37 ± 0.16 2.82 ± 0.09 3.58 ± 0.09 3.89 ± 0.08 3.98 ± 0.12
Area of the film = 1.76 cm2 .
Films were examined by Scanning electron microscopy and x-ray diffractometry after the exposure of 6 weeks. 3. Results and discussion During preparation of drug–polymer dispersion a sufficient time under magnetic stirring was allowed for uptake of the plasticizer by the polymer (in the form of a viscous liquid) for formation of a homogeneous plasticized system [28]. Ideal plasticizers should be miscible and compatible in all proportions with plastic components [29]. In drug–polymer liquid polymer atoms were arranged in a random way similar to the disorder we find in a liquid solution and the incorporated plasticizer in this amorphous phase of polymer, modified its amorphous halo [30]. The thin films were easily removed from the cast plate and the film morphology was described by scanning electron microscopy and polarized light microscopy for the phase behavior, solid state miscibility and/or crystal growth of the drug in the polymer matrix in submicron level in the following sections. X-ray diffractometry studies were described to evident any trace of crystallinity of the drug in the film. 3.1. Physical characterization of the films Results of physicochemical properties of the plasticized hydroxypropyl methylcellulose films have been summarized in Table 2. The thickness and weight of all the film samples were found uniform within each formulation and varied between 0.209 and 0.242 mm in thickness and 41.6 to 52.3 mg (1.76 cm2 ) respectively. All film formulations were translucent and colourless exhibited good folding endurance exceeding 200, indicating that they were tough and flexible and not brittle. The surface pH of the films ranged from 7.10 to 7.43 and hence no mucosal irritation was expected [31] and the films could be utilized as transmucosal drug delivery system. The moisture uptake of the films was monitored at different ambient relative humidity (RH) values of 74, 79 and 84% and as expected, moisture uptake has been increased as the RH increased. Low equilibrium moisture content ranged from 2.37 to 3.98% in the films at laboratory ambient condition can protect the film from microbial contamination. Again small moisture content helps the film to remain stable without being completely dried and brittle. Ttea30 absorbed the highest moisture (moisture uptake) at all RH when compared to other films (4.86, 8.04 and 10.79% respectively). The uptake of water vapor by the film depends mainly on the chemical structure of the components of the matrix. Moisture held in the film forms hydrogen bond with the polymer chains of HPMC plasticized with soluble compound. 3.2. Film morphology In the present study, Tpg10 , Tpg30 , Tdmso30 , Tpeg30 or Ttea30 formed the polymer matrix film, whereas the drug particle was the
dispersed phase. Good dispersion of drug, effective wetting of drug particle by the polymer, and strong interfacial adhesion between two phases were required to obtain satisfactory drug delivery properties. To study the distribution and the phase size of drug crystal particle in the polymer matrix, cast film surfaces influenced by the plasticizer were examined with both of polarized light microscopy and scanning electron microscopy. Light micrographs of telmisartan drug crystals and the surface layer of the freshly prepared films have been depicted in Fig. 1a–f. Distinct crystalline structure of pure telmisartan has been observed in Fig. 1f. All the surface layers were almost relatively smooth without any significant surface porosity compared to Tpg10 (Fig. 1a). The trace amount of small drug particles spread in the polymer matrix was observed. They were lacking of definite shape, organization and distinct crystalline structure. Appearance of microparticles was very much less prominent in Tpeg30 , Tdmso30 , and Ttea30 compared to Tpg10 and Tpg30 . The structure and morphology results of all the HPMC matrix film samples showed crack-free at the submicron level of Tpg30 , Tdmso30 , Tpeg30 and Ttea30 (SEM photomicrographs in Fig. 2a–h). The Tpeg30 film (Fig. 2c and d) displayed a relatively smooth surface, whereas the films Tpg30 , Tdmso30 and Ttea30 were rougher (Fig. 2 a, b, e, f, g, and h). As displayed in the figure (Fig. 2 a, b, e, and f) the drug crystallites were almost rod shaped and scattered throughout surface of the film. But the drug crystallites found in Tpeg30 and Ttea30 were almost plate shaped and scattered in the film. Most of the drug crystallites were in the fused appearance might be due to the polar surface of the cellulose fibers (HPMC) and drug. It has been suggested that the individual drug crystallites were held in the HPMC domain largely by hydrogen bonding. SEM micrograph of HPMC control film produced by Bilbao-Sáinz et al. [32] displayed a relatively smooth surface rather than the matrix in the MCC-reinforced nanocomposite films. The morphology of the HPMC control film (without any plasticizer) prepared from an aqueous solution analyzed by SEM exhibited a high degree of porosity evenly distributed throughout the film [33]. The results of the present study indicated that with the addition of plasticizers (containing hydroxyl or amino functions) has further influenced the decrease of crystallinity of the drug, and an increase in the flexibility of the films might be owing to the decrease in the number of weak inter- and intramolecular hydrogen bonds of the base polymer HPMC and drug.
3.3. X-ray diffraction studies X-ray diffraction pattern of pure telmisartan and formulated freshly prepared films has been displayed in Fig. 3. The pattern of pure drug exhibited high intensity reflections with characteristic peaks at 10.87◦ , 18.20◦ , 26.37◦ , 42.25◦ , 48.38◦ and 68.75◦ (2Â) in the angle range of 10–70◦ (2Â). The pattern of physical mixture of drug and polymer (Tpm, 1:3) did not present any significant difference compared to crystalline telmisartan (slightly poor in reflections of 2Â at 10.86◦ , 18.22◦ , 26.25◦ , 42.25◦ , 48.37◦ and 68.76◦ ).
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Fig. 1. Polarized light micrographs of telmisartan pure drug crystals and films prepared using different plasticizers in HPMC matrix (a) Tpg10 ; (b) Tpg30 ; (c) Tpeg30 ; (d) Tdmso30 ; (e) Ttea30 ; and (f) Tel. All magnifications at 400× with an exposure time of 0.2 s.
The XRD pattern of the films containing different plasticizer has shown significantly reduced reflections of the drug due to presence of hydroxypropyl methylcellulose in all the films in the same drug–polymer ratio (1:3). The status of the polymer (HPMC) in the film was in the amorphous phase. Parameswara et al. [34] also found very poor intensity reflections in the XRD pattern of the polymer upon addition of PEG as plasticizer in HPMC films (without drug). Bragg peaks appeared on the top of an amorphous halo in the diffractograms of the film samples. X-rays were scattered in many directions leading to a large bump distributed in a wide range (2Â) instead of high intensity narrower peaks. Tpg10 and Tpg30 films have presented almost same pattern (2Â: shouldering at 24.0◦ and some moderate reflections at 42.12, 48.37 and 68.81◦ ). The peaks intensity of Tpeg30 (2Â: shouldering at 26.45◦ and some reflections at 42.13, 48.36 and 68.75◦ ) were comparatively less than Tdmso30 (2Â: shouldering at 24.1◦ and the reflections at 42.25, 48.37 and 68.74◦ ). DMSO does not contain hydrogen bond donor functionality and easily can form solvent cavities to accommodate a drug in DMSO than in water. The large dielectric constant of DMSO is energetically favorable to the interaction of DMSO with telmisartan that contains dipole. Telmisartan structure is asymmetric and the molecule has polarity [35]. Benzimidazole rings of telmisartan provide some enhanced hydrophobic binding.
The film formulation Ttea30 (2Â: shouldering at 25.99◦ and the reflections at 42.25, 48.38 and 68.75◦ ) showed maximum amorphization of telmisartan. Therefore, XRD results testified the reduced ordering of the crystal lattice as: The litTel > Tpm > Tpg10 > Tpg30 > Tdmso30 > Tpeg30 > Ttea30 . erature survey also revealed that the effect of polypropylene glycol used as a plasticizer on a decrease in crystallinity was lower than in PEG [36]. The steric hindrance and miscibility of the plasticizers, through their different polar functions, were the two major characteristics that could be related to the slight difference in lattice spacing of the reflections in the XRD pattern of the formulated films. Increased elongation at break (flexibility) and soft and ductile polymeric films have been produced after effectively destroying polymer crystals when the films were plasticized [37]. 3.4. Thermal analysis Fig. 4 shows the thermograms from DSC analysis of pure crystalline drug telmisartan and the film formulations. The endothermic peak observed at 269.4 ◦ C for the crystalline form corresponds with literature data regarding the melting point of Tel [38]. In the films, no endothermal peak for Tel was observed in the vicinity at 269.4 ◦ C suggesting possible molecular
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Fig. 2. Visualization of surface morphology of the fresh films by scanning electron microscope: (a) Tpg30 (magnification 500×); (b) Tpg30 (magnification 5000×); (c) Tpeg30 (magnification 500×); (d) Tpeg30 (magnification 5000×); (e) Tdmso30 (magnification 500×); (f) Tdmso30 (magnification 5000×); (g) Ttea30 (magnification 500×); (h) Ttea30 (magnification 5000×).
dispersion of Tel in polymer–plasticizer combination. Large shallow broad endothermic effects, over the temperature range 50–110 ◦ C, attributed to the removal of moisture due to the presence of HPMC in the films [39]. A small step-like behaviour at about 220 ◦ C was a manifestation of the glass transition of Tel observed in the films Tpg10 , Tpg30 , Tpeg30 and Tdmso30 . Endothermic event at around 220 ◦ C was not observed in the film, Ttea30 containing triethanolamine as plasticizer.
3.5. In-vitro dissolution studies In vitro dissolution of drug in the simulated fluid (buffered at pH 7.4 and 37 ◦ C: biologically relevant) is more important rather than the film solubility in water as a whole if it is a film type drug delivery system [26]. Plasticized-HPMC matrix system plays an important role in controlling drug dissolution from the film. In-vitro dissolution profiles of all the film formulations have been depicted in Fig. 5.
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Fig. 5. In-vitro drug dissolution profiles of plasticized-HPMC film (Tpg10 , Tpg30 , Tpeg30 , Tdmso30 and Ttea30 ).
3.6. Stability analysis of the films
Fig. 3. The XRD pattern of telmisartan crystalline drug (Tel), physical mixture of Tel and HPMC in 1:3 ratio (Tpm), and the formulated films (Tpg10 , Tpg30 , Tpeg30 , Tdmso30 , Ttea30 ).
Triethanolamine improved the drug dissolution to the great extent (98%) compared to the least by propylene glycol. The order of dissolution was observed as Tpg10 < Tpg30 < Tpeg30 < Tdmso30 < Ttea30 . Reduced crystalline intensity of Tel (poorly soluble drug) to the maximal extent in Ttea30 brought about maximum dissolution of drug and the result was also supported by XRD and thermal analysis.
Significant changes in the micrographs have not been observed after the exposure of the films at 40 ◦ C/75% RH for 6 weeks (Fig. 6a–h). All the films were crack-free at the micrometer level. The similar type of surface roughness as of freshly prepared films has not been changed severely in Tpg30 (Fig. 6a and b), Tdmso30 (Fig. 6e and f) and Ttea30 (Fig. 6g and h), whereas, Tpeg30 (Fig. 6c and d) film appeared comparatively smooth. The prominent submicron and nano-pores were much larger in Tpg30 compared to Ttea30 films. Almost rod shaped drug crystallites were consistent in Tpg30 and Tdmso30 film as observed in the fresh. The consistency of plate shaped crystallites was also noticed in Tpeg30 and Ttea30 after 6 week exposure of stressed condition of 40 ◦ C/75% RH. XRD pattern of the films after 6 weeks (40 ◦ C/75% RH) revealed no significant change in the film (data not shown) and the reduced ordering of crystallinity were: Tel (fresh) > Tpm (fresh) > Tpg10 > Tpg30 > Tdmso30 > Tpeg30 > Ttea30 . The growth of micro- and nano-crystallites of telmisartan in the films has been arrested might be due to the hydrogen bonding with the cellulose fibers of HPMC even in the favorable environment of 40 ◦ C/75% RH. Adsorption of moisture by the films (40 ◦ C/75% RH, 6 w) could not
Fig. 4. DSC thermogram of pure drug (Tel) and formulated films (Tpg10 , Tpg30 , Tpeg30 , Tdmso30 and Ttea30 ).
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Fig. 6. Surface morphology of the films by scanning electron microscope after 6 weeks of exposure at 40 ◦ C/75% RH: (a) Tpg30 (magnification 500×); (b) Tpg30 (magnification 2000×); (c) Tpeg30 (magnification 500×); (d) Tpeg30 (magnification 2000×); (e) Tdmso30 (magnification 500×); (f) Tdmso30 (magnification 2000×); (g) Ttea30 (magnification 500×); (h) Ttea30 (magnification 2000×).
bring about molecular mobility of the energetically trapped glassy phase of the drug significantly. The diffusion of small molecules (telmisartan) through the polymer matrix was very slow and could not be accelerated by water. PEG was found more suitable as chitosan plasticizer compared to PG and ethylene glycol, and the chitosan film was reported to be stable until 9 weeks of storage at ambient condition of 22 ◦ C, 40–60% RH [40].
4. Conclusions Effect of plasticizers such as propylene glycol, polyethylene glycol 400, dimethyl sulfoxide and triethanolamine on crystallinity of telmisartan in HPMC matrix films was examined using PLM, SEM, and XRD. The Tpeg30 film produced a relatively smooth surface in comparison to the other films in submicron level. Both
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water-soluble HPMC and plasticizer were compatible with the drug and did not phase separate upon solvent evaporation. PlasticizedHPMC has a major role in the significant inhibition of crystal growth of drug in the film. The good solid state miscibility of drug and polymer in the film is technologically advantageous owing to its decreased possibility to lead pore formation from polymer leaching during water immersion. Based on all the results, the increased order of amorphization of drug was observed in the film formulation as: Tpg10 < Tpg30 < Tdmso30 < Tpeg30 < Ttea30 . Relatively amorphous state of telmisartan in Ttea30 formulation in presence of triethanolamine as plasticizer is technologically more advantageous than the others owing to its anticipated better bioavailability. Although it is a thermodynamically unstable state, a physical stability study at 40 ◦ C/75% RH for 6 weeks revealed no significant change of the amorphous phase of the drug in Tpg30 , Tdmso30 , Tpeg30 and Ttea30 films. Acknowledgments The authors are very much grateful to Prof. Manoj Ranjan Nayak, President, Siksha O Anusandhan University for his encouragement and facilities. References [1] S. Bohic, P. Weiss, P. Roger, G. Daculsi, J. Mater. Sci. M 12 (2001) 201–205. [2] R. Chandak, P.R. Verma, Yakugaku Zasshi 128 (2008) 1057–1066. [3] B. Luppi, F. Bigucci, M. Baldini, A. Abruzzo, T. Cerchiara, G. Corace, et al., J. Pharm. Pharmacol. 62 (2010) 305–309. [4] Y. Amouriq, X. Bourges, P. Weiss, J. Bosco, J.M. Bouler, G. Daculsi, J. Mater. Sci. M 13 (2002) 149–154. [5] P. Weiss, P. Layrolle, L.P. Clergeau, B. Enckel, P. Pilet, Y. Amouriq, Biomaterials 28 (2007) 3295–3305. [6] S.Y. Lin, Ch.J. Lee, Y.Y. Lin, Pharmaceut. Res. 8 (1991) 1137–1143. [7] M. Rahman, Ch.S. Brazel, Prog. Polym. Sci. 29 (2004) 1223–1248. [8] P.K. De, S. Mallick, B. Mukherjee, S. Sengupta, S. Pattnaik, S. Chakraborty, Iranian J. Pharm. Res. 10 (2011) 193–201. [9] S. Pattnaik, K. Swain, A. Bindhani, S. Mallick, Drug Dev. Ind. Pharm. 37 (2011) 465–474. [10] P.V.A. Bergo, P.J.A. Sobral, Food Hydrocolloid. 21 (2007) 1285–1289.
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