Synthesis, characterization and sustainable drug release activity of drug bridged diblock copolymer
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Ring opening polymerization of ε-caprolactone and tetrahydrofuran were carried out by bulk polymerization technique in the presence of a drug molecule as an initiator at 160 °C for 2 h under nitrogen atmosphere. The synthesized homo and diblock copolymer was characterized by various analytical techniques. Further, the sustainable drug release study was carried out at gastric pH of 7.2. The diblock copolymer formation was confirmed by the appearance of aromatic C=O stretching around 1680 cm−1. Due to the hydrophilic nature the diblock copolymer exhibited lower melting temperature. The drug release study confirmed the first order drug release model.
KeywordsROP Copolymer FESEM TGA Tensile strength Drug delivery
Poly(ε-caprolactone) (PCL) has wide applications in bio-medical engineering field as a drug carrier material because of its bio-degradability and bio-compatibility. Such a bio-medically important candidate is prepared by ring opening polymerization (ROP) method through co-ordination insertion mechanism. For this purpose stannous octoate (SO) is used as a catalyst in the presence of different initiator species. ROP of CL was reported in the presence of n-butanol as an initiator [1, 2]. Terzopoulu et al.  reported the ROP of CL using SO as a catalyst and initiator. Similarly, other novel initiators such as benzylalcohol [4, 5], gelatin , lipase , mercaptohexanol , diethyleneglycol , bisphenolate ligand  and mPEG  were used for the ROP of CL. Due to the bio-degradability and bio-compatibility of PCL, it is used as a drug carrier material. Any drug molecule can be loaded on the backbone of PCL through a hydrogen bonding mechanism. But the drawback is it releases all the drug molecules immediately which lead to overdose of drug. This leads to the unwanted side effects to patient sometimes. Hence, sustainable release of drug is essential. For this purpose, the drug molecule should be chemically conjugated using hazardous organic solvents. But, this technology is highly expensive. In 2013, Sawdon et al.  reported the guanosine, an antiviral acyclovir initiated ROP of CL. Folicacid initiated ROP of CL was reported . The drug delivery study proved to be sustainable in release of drug in the given buffer medium. By keeping this idea in mind, the present investigation was made as a development of this idea. The literature survey reports that few reports are available on the drug initiated ROP of CL. This urged the authors to do the present investigation.
Poly(tetrahydrofuran) (PTHF) secured second rank in the polymer class in the bio-medical field because of its non-cytotoxic effect and bio-compatibility. PTHF can be synthesized by cationic ROP technique. In 2012, Nomura et al.  used V complexes as an initiator/catalyst for the ROP of THF. Different initiating systems such as keggin type heteropolyacids , cationic species , norbornyl cation , magamite-H+ , glycosyl  and aminoacids [20, 21, 22] were used for the ROP of THF. Recently, dye initiated ROP of THF was reported in the literature . In 2015, folicacid initiated ROP of CL was reported by Kailash et al. . The literature survey declares that no report on drug initiated ROP of THF is available in the literature except folicacid . The novelty of the present investigation is drug molecules with different functional groups are used as an initiator for the ROP of THF with sustainable drug release.
In bio-medical engineering field, amoxicillin (amox) is used as an antibiotic particularly for the treatment of bacterial infection diseases. Time dependent release of amox was studied . Controlled release of amox from modified cellulose was reported in the literature . Gentamicin (gen) or garamicin is an antibiotic used for the treatment of pneumonia, urinary tract infections and bacterial infectious diseases. Controlled delivery of gen using poly(3-hydroxybutyrate) microspheres  was reported in the literature. Gentamicin sulphate release from PVA hydrogel was reported . Neomycin (neo) is an antibiotic with two or more aminosugar which are connected through glycosidic linkages. Neomycin release from PVP hydrogel study was done by Choi et al. . Chitosan nanofiber containing neomycin sulfate release study was reported in the literature . The literature survey reported that drug bridged diblock copolymer based carrier material was not used for amox, gen and neo with sustainable releases. This tempted the authors to concentrate on sustainable release of the above mentioned drugs.
2.2 Synthesis of homopolymer and diblock copolymer
FTIR spectra were recorded with the help of Shimadzu 8400 S, Japan model instrument by KBr pelletization method from 400 to 4000 cm−1. 3 mg of copolymer was ground with 200 mg of spectral grade KBr and made into disc under the pressure of 7 tons. The melting temperature (Tm) of the polymer samples was determined using DuPont Thermal Analyst 2000 Differential Scanning Calorimeter 910S (USA) model instrument. All the measurements were made under N2 atmosphere in the temperature range of RT to 100 °C with 10 °C/min heating rate. The NMR spectrum was recorded with the help of Bruker Biospin High Resolution Digital 300 MHz NMR Spectrometer (USA) using dueterated chloroform (CDCl3) as the solvent and tetramethyl silane (TMS) served as an internal standard. Thermal stability of polymer was measured using DuPont 951 thermo gravimetric analyzer (USA). Thermograms were recorded under air atmosphere in a temperature range of 30–800 °C at the heating rate of 10 °C/min. Surface morphology of the sample was measured by JSM 6300 (Jeol product) SEM instrument. UV–visible spectrum was measured by using Shimadzu 3600 NIR spectrophotometer (Japan). Field emission scanning electron microscopy (FESEM) with EDX was used to examine morphological behavior of polymer with the help of FESEM (Hitachi S4800, Japan).
2.3.1 Drug release study
The following plots were made in order to determine the model of drug release model and their flow mechanisms which were drawn and their slope and intercept values were noted: zero-order model was the plot of (% CDR) versus time; first-order model was the plot of log(% drug remaining) versus time; the Higuchi model was the plot of (% CDR) versus (time)1/2; the Hixson-Crowell model was the plot of (% drug remaining)1/3 versus time; and the Korsemeyer–Peppas model was the plot of log(% CDR) versus log(time).
2.3.2 Mechanical property
The mechanical properties were measured by Universal Tensile Tester, Deepak Polyplast, India. Three samples were measured according to the ASTM standard. The average is considered here.
3 Results and discussion
3.1 FTIR spectroscopy
The FTIR spectrum of Gen end capped PCL is shown in Fig. 1c. Table 1 shows the peak corresponding to PCL. A broad peak around 3560 cm−1 accounts the O–H stretching of Gen. The C-H symmetric and anti-symmetric stretching appeared at 2865 and 2948 cm−1 respectively. Peaks corresponding to PCL are also observed. The ester C–O–C linkage can be seen at 1187 cm−1. Figure 1d indicates the FTIR spectrum of PCL-Gen-PTHF diblock copolymer (Table 1), and here also the above said peaks were observed. Apart from the regular peaks some new peaks were also observed. Peaks at 2524 and 2645 cm−1 are due to C-H symmetric and anti-symmetric stretching respectively of aromatic phenyl ring. The carbonyl stretching at 1692 cm−1 is due to the carbonyl stretching of PAH units. Another one important peak appeared at 1589 cm−1 which is due to the formation of tetrahydrofuroniam ion . The aromatic C–H bending was noted at 662, 734, and 796 cm−1. Thus the appearance of new peaks such as aromatic C–H, doublet formation, C–O–C stretching, and aromatic stretching confirms the ROP of THF in the presence of Gen end capped PCL as a chemical initiator.
Neo contains O–H, –NH2 and ether like functional groups. The O–H group of Neo is more effective towards the ROP of CL. The FTIR spectrum of Neo end capped PCL is given in Fig. 1e. The O–H stretching,–CH stretching, C=O stretching,–C–N stretching, and C-H OPBV are observed at (3644 cm−1, 2872 cm−1 and 2955 cm−1, 1731 cm−1, 1361 cm−1 and 728 cm−1) (Table 1) respectively. The FTIR spectrum of PCL-Neo-PTHF diblock copolymer is given in Fig. 1f. Here also the above said peaks corresponding to PCL appeared (Table 1). New peak such as aromatic C–H stretching at 2533 cm−1 and 2673 cm−1, aromatic C=O stretching at 1693 cm−1 and aromatic C–H bending at 665 and 801 cm−1 appeared respectively. The aliphatic C–O–C linkage appeared at 1194 cm−1 . Thus the FTIR spectrum confirmed the homopolymer and copolymer formation.
3.2 DSC study
Tm, molecular weight and mechanical property data
3.3 TGA study
3.4 SEM and FESEM image analysis
3.5 EDX spectrum
3.6 GPC study
3.7 NMR study
3.8 Tensile strength
The alternate aim of the current study is to test whether the polymer system is suitable for the splinting activity. The splinting activity needs good mechanical properties. The raw fabric exhibited the average tensile strength (TS) value of 1846.45 kg/cm2 with 38.45% of elongation. In this case the homopolymer coated fabric exhibited a tensile strength value of 5450.68 kg/cm2 with %elongation value of 19.72% (Table 2). After the coating the fabric exhibited 2.5 times higher tensile strength value due to the hydrophobic nature of PCL. Unfortunately, the % elongation value dropped suddenly. This can be the brittle nature of the PCL coated fabric. The diblock copolymer coated fabric exhibited the tensile strength and % elongation values of 5000 kg/cm2 and 42.19% respectively. The present system yielded lower tensile strength value than the PCL coated fabric. This can be explained on the bases of increased moisture absorbing [20, 21, 22] capacity of diblock copolymer grafted fabric. The moisture content destabilized the tensile strength value. It means, after the diblock copolymer formation, the flexibility and amorphous characteristic of the polymer have increased. This leads to the increase in % of elongation .
3.9 Drug release study
Drug release data of PCL-Amox-PTHF system
− 1.23 × 10−4
− 3.93 × 10−4
Similarly, the other homopolymer and diblock copolymer systems having different drug molecules were subjected to drug delivery study and the data was summarized in Table 2. From the table it was found that all the drug bridged systems followed the first order model with Fickian drug transportation mechanism. This is purely based on the hydrolysis reaction because the drug molecules are chemically attached with the polymer backbones. The n values of PCL-Gen and PCL-Gen-PTHF systems, determined from the Korsemeyer and Peppas model plot was 0.47. This confirmed the Fickian diffusion mechanism. From the drug release study one can come to a conclusion that the Gen was released from the diblock copolymer backbone via hydrolysis reaction. The Gen was solubilized in the given medium and released from the diblock copolymer. The drug release activity of PCL-Neo and PCL-Neo-PTHF systems were studied under gastric pH. The data is given in Table 3. Various models were tried and the First order model exhibited the maximum R2 value (0.988). The slope value of the Korsemeyer-Peppas model plot was found to be 0.35, which confirmed the Fickian drug transport mechanism. In the case of diblock copolymer system, again the First order model exhibited the max R2 value. Further, the drug release mechanism was confirmed by drawing the Korsemeyer–Peppas model plot with the slope value 0.26. This explained the Fickian transport mechanism of drug. The present system concluded that both the homopolymer and diblock copolymer exhibited the Fickian transport mechanism of drug with First order drug release model. The drug release activity of diblock copolymer is induced through the soft segments like THF. Since it is a hydrophilic in nature there exist a thorough mixing with the drug release medium. First, the hydrolysis started with THF segments followed by the junction of a drug and PTHF. Now the one end of the drug is free whereas the other end is conjugated with the PCL, is considered as a heterogeneous hard segment. Here the hydrolysis started with the junction of drug and PCL followed by the CL segments. The hydrolysis of PCL-drug takes some time to interact with the reaction medium. Finally, both ends of the drug are free from polymers and are released into the reaction medium. In the case of homopolymer, the hydrolysis starts at the junction of drug and PCL followed by the CL segments. The important point to be noted here is the drug release activity do not only depend only on the nature of the polymer but also depends on the molecular weight of the polymers. The coil like structure of polymer plays a vital role in the interaction with the reaction medium and finally the drug gets released. In such a way the sustainable drug release activity of diblock copolymer is attained through hydrolysis mechanism. In 2015, Kailash et al.  studied the sustainable drug release activity of diblock copolymer, in which they reported the Hixon-Crowell model drug release with Fickian drug transportation mechanism. The present investigation is entirely different from the literature report . This is associated with the nature, size and number of functional groups present in the drug as well as the pH of the drug release study.
The important points are summarized and presented as the conclusion. The FTIR spectrum showed a peak corresponding to the tetrahydrofuronium ion around 1580 cm−1 which confirmed the diblock copolymer formation. The 1H-NMR spectrum showed a peak at 4.1 ppm corresponding to the –OCH2 proton signal of PCL. The Tm of homopolymer is greater than that of diblock copolymer due to the hydrophobic nature of PCL. The diblock copolymer exhibited a two step degradation process due to the degradation of PCL and PTHF segments. The Mw of diblock copolymer is greater than that of homopolymer. The SEM image showed the broken stone like morphology for PCL. The EDX spectrum showed the presence of N and S which confirmed the presence of drug molecules in the diblock copolymer as an initiator species. The tensile strength of homopolymer is greater than that of diblock copolymer is due to hydrophobic nature. The diblock copolymer exhibited high % elongation value due to the hydrophilic nature. Both the homopolymer and diblock copolymer systems followed the first order drug release model with Fickian drug transportation mechanism.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
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