Synthesis, characterization and formulation of sodium calcium silicate bioceramic for drug delivery applications

2.1 Preparation of sodium calcium silicate

One molar stock solution of calcium nitrate [Ca(NO₃)₂·4H₂O; 99%, AR, Rankem, India], sodium silicate (Na₂SiO₃·xH₂O; 99%, AR, Merck, India) and citric acid (C₆H₈O₇; 99.7%, AR, SRL, India) was prepared by dissolving the salts in demineralised water at room temperature. Equal volumes of sodium silicate, calcium nitrate and citric acid solutions were pipetted into a glass beaker, and the pH of the solution was adjusted to 1 by adding concentrated nitric acid. The clear solution was kept in the pre-heated muffle furnace at 300°C. Within few minutes, the solution underwent combustion by self-propagating auto-ignition and formed a black, fine precursor. Given that the reaction is highly exothermic, the reaction was performed inside a closed furnace with a suitable exhaust system to remove the evolved gases. The precursor was kept for heat treatment at 900°C for 6 h.

2.2 Formulation and drug loading

To mimic the composition of the human bone, the scaffolds were prepared by replacing hydroxyapatite with sodium calcium silicate and collagen with polyvinyl alcohol. Scaffolds with different ratios of sodium calcium silicate and PVA were made to optimize the ratio of bioceramics and biopolymers. Ciprofloxacin was used as the model drug to investigate the drug release kinetics of sodium calcium silicate.

A total of 100 mg of ciprofloxacin was dissolved in 100 ml of water, and 1 g of PVA was dissolved in hot water. The resultant solution was allowed to cool and then made up to 100 ml for use as a stock solution for further experiments. To achieve thorough distributions of the drug in both the ceramic and polymer matrix, the volume of the solution containing 5 mg of the drug solution was added to the sodium calcium silicate powder and made into slurry. Different ratios of the polymer solution were added to the slurry and thoroughly mixed using mortar and pestle. The resultant slurry was dried at 60°C for 6 h in a hot-air oven. Four slurries with 5%, 10%, 15% and 20% weight ratio of the polymer and 5 mg of the drug content were prepared and pelletized in a hydraulic press. By following this procedure, 5 mg of ciprofloxacin was loaded uniformly throughout the matrix in all four scaffolds.

2.3 Drug delivery studies

Scaffolds with different concentrations of the polymer were placed in 50 ml of the simulated body fluid (SBF) taken in four different conical flasks and incubated at 37.5°C for 10 days. Every 24 h, 2 ml of the sample was collected from the flask and replaced with the fresh SBF of the same volume. The collected sample was analyzed using a UV-visible spectrometer at 278 nm to determine the release kinetics of the drug from the scaffolds. Using the absorbance values, the amount of drug released was determined for 10 days [19–23].

3.1 Synthesis of bioceramic

Sodium calcium silicate was synthesized by the rapid combustion method using citric acid as fuel. Citric acid plays a dual role in the synthesis because it does not only function as a reducing agent, but also avoids the precipitation of ions by complexing with metal ions. The vigorous redox reaction between fuel and oxidant mixture at the time of combustion gives rise to a very high local temperature with the evolution of large volume of gases. In the present study, although the furnace temperature was maintained at 300°C, the particles could have attained higher local temperatures (approximately 1500°C) during auto-ignition. A large amount of heat was released during the combustion, which produced an intense local heating that enhanced the phase formation. The volume of gas generated and the increase in the local temperature due to combustion depend on various factors, such as the nature of the fuel, temperature, water content and the ratio of fuel to oxidizer, because the thermochemistry of combustion is different for different fuels. This was evident from the sudden increase in temperature inside the furnace from the set temperature of 300 to 500°C during combustion.

The precursor formed after combustion was calcined at 500°C to eliminate the remaining organic constituents present in the product, which results in the formation of sodium oxide, calcium carbonate and amorphous silica. Subsequently, the sample was calcined at 900°C for 6 h to aid the phase formation of sodium calcium silicate from the products of intermittent calcination.

3.2 Characterization of the bioceramic

The phase purity of the synthesized sodium calcium silicate was confirmed by the powder X-ray diffraction (XRD) patterns (Figure 1). The XRD pattern of the sodium calcium silicate was matched with that of the standard JCPDS file (24-1069). The major phase formed was sodium calcium silicate, and trace amount of larnite was present as an impure phase.

Figure 1

XRD pattern of the sodium calcium silicate synthesized by rapid combustion method.

3.3 Bioactivity of the scaffolds

The scaffolds were made with different concentrations of polymer and sodium calcium silicate (Table 1). In all the scaffolds, the concentration of ciprofloxacin was uniform and only the concentration of polyvinyl alcohol was varied. The scaffolds were placed separately in 50 ml SBF, and the samples’ absorbance was analyzed at 278 nm every 24 h. The concentration was calculated by plotting a graph between time vs.% release.

Hydroxylapatite was the major constituent deposited on the scaffold in the physiological environment. Consequently, the deposition of hydroxyapatite on the surface of the sodium calcium silicate/PVA scaffolds was analyzed periodically_. After incubation in SBF for about 10 days, the scaffolds were analyzed by XRD to check for the formation of hydroxyapatite on their surfaces. Formation of apatite on the surface of bioceramics in SBF depends on various factors, such as super-saturation of the solution, surface energy of the substrate and interfacial energy of the substrate. An important issue that should be mentioned here is the formation of calcite accompanying the formation of apatite. Interaction between bioactive materials and physiological solutions in vitro is known to occur in two steps: dissolution and back precipitation. In the dissolution step, ions are released from the material into the surrounding solution, which will change the local pH and ionic concentration at the material solution interface and then promote the back precipitation of a bone-like apatite layer onto the surface of bioactive materials. The composite BCP20 has a ratio of 80:20 of sodium calcium silicate and polymer, which is close to that of the human bone [70% hydroxyapatite (bioceramic phase) and 30% collagen (organic phase)].

The XRD pattern shows the formation of calcium apatite phases on the surface of all the scaffolds, confirming its bioactivity (Figure 2). However, the relative intensity of sodium calcium silicate peaks compared with that of hydroxyapatite peaks indicates the effectiveness of the scaffold as its composition varies. Compared with the other formulations, BCP20 shows more calcium apatite deposition as the composition comes closer to that of the natural bone. BCP15 exhibits less calcium apatite deposition, indicating that it has lesser bioactivity, which may be due to the deviation in concentration of the polymer from that of the natural bone. BCP10 has a moderate calcium apatite formation on its surface, whereas BCP5 shows broad peak in the XRD pattern. This trend observed in these two scaffolds might probably be similar to that found in BCP15.

Figure 2

XRD pattern showing the bioactivity of different formulations of sodium calcium silicate.

3.4 Drug delivery kinetics of the scaffolds

The release of drug from the ceramic matrix will follow the dissolution pathway, whereas that from the polymer matrix will follow the diffusion pathway. In the present system, the matrix contains both the constituents so the release kinetics may get altered depending on the ratio of ceramic to polymer. The drug release profile of all the compositions shows almost a similar kind of release, but the scaffold BCP20 shows the least release compared with the other scaffolds (Figure 3). This observation may be attributed to the high polymer concentration in the scaffold, which led to the diffusion of the drug from the matrix, resulting in the sustained release of the drug. The scaffold BCP5 shows the highest release because its polymer concentration was low. Consequently, the dissolution pathway predominates, resulting in maximum drug release. Moreover, there was a burst in the release of ciproflaxocin from all the compositions at the onset of the experiment, as 18% of the drug was released within 24 h in all compositions. The release pattern of the drug from the different scaffolds shows similar trend with very small variation. Therefore, the drug release kinetics is independent of composition.

Figure 3

Drug release kinetics of different formulations of sodium calcium silicate.

3.5 Simulation studies of drug delivery kinetics

A mathematical model is a description of a system using mathematical language, and the process of developing a mathematical model is termed mathematical modeling. Mathematical modeling of drug delivery and predictability of drug release is a field of steadily increasing academic and industrial importance with an enormous future potential. Due to the significant advances in information technology, the in-silicon optimization of novel drug delivery systems can be expected to significantly improve its accuracy and easiness of application. Analogous to other scientific disciplines (e.g., aviation and aerospace), computer simulations are likely to become an integral part of future research and development in pharmaceutical technology. It is only a question of time when mathematical programs will be routinely used to help in optimizing the design of novel dosage forms. Considering the desired type of administration, drug dose to be incorporated and targeted drug release profile, mathematical predictions will allow for good estimates of the required composition.

There is no mathematical model available that considers the nature of two different (polymer and ceramic) constituents of the composite, porosity of the matrix, particle size of bioceramics and diffusion of drug in composite matrix. The major problem in designing a model for the delivery system of ceramic drug arises because of the bioactivity of the system: as the deposition of apatite layer takes place on the surface it will affect the diffusion of drug and porosity of the system, hence the model cannot be employed for the data obtained for the entire period.

The mathematical modeling employed here is based on the hypothesis proposed for thin films [24–26], and most of the criteria defined for this model are satisfied by the present system. Accordingly, the model expression is given by

where M_t is the amount of drug released until the time t, A is the release area, D is the drug diffusion coefficient, C₀ is the initial drug concentration in the matrix, and C_s is the drug solubility.

This model expression is semi-empirical as it uses both the theoretical and practical data in predicting the values using this model. A particularly fruitful, but also very challenging aspect is to combine the mathematical theories with models quantifying drug transport in the living organism, including drug distribution in the various organs and even within the different cell compartments. Ideally, theoretical calculations should allow for a quantitative prediction of the effects of formulation and processing parameters not only on the resulting drug release kinetics, but also on the resulting drug concentration time profiles at the site of action in the human body and on the pharmaco-dynamic effects in the patients under the disease conditions. This type of mathematical modeling is much more complex, but in the very long run it could help to allow for customized drug delivery to the patient.

In this study, mathematical modeling was performed for all the formulations (Figure 4). The model shows that the real-time and the theoretical values are well correlated for all the samples, proving that the model is valid for this system.

Figure 4

Simulated drug release profile of different formulations of sodium calcium silicate.