1. Introduction
Tablets have been an attractive choice for pharmaceutical manufacturing over several decades and are a commonly used dosage form for drug administration. Consideration of the tableting approach is dependent on the characteristic properties of the active pharmaceutical ingredient (API), the excipients, and their stability during the manufacturing process [
1]. Direct compression (DC) is the preferable method for tablet preparation since it requires fewer processing steps, avoids exposure to heat and moisture, resulting in good stability of the therapeutic drug [
2], and offers lower production costs. Nevertheless, API that can be processed into tablets by DC are limited due to poor flowability and compactibility properties. Thus, excipients that enhance powder flowability and compactibility are required in order to increase the use of DC in tablet production and ensure robust manufacturing [
1]. Although, many DC carriers are commercially available, most of them cannot be classified as multifunctional excipients; thus, several excipients have to be used in a DC formulation in the tablet manufacturing industry.
Currently, particle engineering in the pharmaceutical industry has become an important topic to control a range of key unit manufacturing operations [
3]. It requires an understanding of particle formation processes. Particle engineering combines many elements of science including chemistry, formulation science, colloid and interface science, heat and mass transfer, solid state physics, aerosol and powder science, and nanotechnology [
4].
The co-processing method is applied to improve the functionality of an existing excipient by combining parent excipients with other tablet excipients using an appropriate process [
5,
6]. Many excipients can be engineered as co-processed excipients to provide the desired properties to be used in DC [
7]. The co-processed excipients are physically modified without chemical structure alteration while they synergistically increase their functional performances [
8,
9]. Thus, a combination of existing excipients, using processing techniques, is an interesting option for new excipient development, which can be brought to market without undergoing the safety and toxicity testing of a completely new chemical.
Plastic and brittle materials are usually employed in the co-processing method to enhance excipient functionality [
9,
10]. Existing excipients of reasonable price and ready availability such as chitosan (plastic material) and kaolin are remarkable choices for particle engineering using the co-processing technique. Chitosan has been accepted as an effective tablet disintegrant due to its high water absorption capacity [
11]. The excellent swelling capacity of chitosan in water was also indicated in a previous study by Rasool et al. [
12]. Kaolin has been used in many pharmaceutical applications as an excipient or active ingredient, because it exhibits excellent surface physicochemical properties and is stable material. Nevertheless, chitosan powder shows poor flow ability of pharmaceutical blends in large-scale production [
13,
14], while tablets containing kaolin as a diluent present poor mechanical strength. A report by Badwan et al. [
13] also pointed out the poor compressibility of chitosan, resulting in tablets with low crushing strength due to the high porosity of chitosan powder.
Co-processed excipients can be produced by many different processing methods. This study concentrates on spray drying, which is the process of choice for well-known commercial co-processed excipients. Spray drying is a widely used technique for novel pharmaceutical excipient development, as it can provide spherical particles in a narrow particle size range including the free flowing agglomerates that are suitable for direct compression method [
15,
16]. Furthermore, spray drying offers several advantages including good reproducibility and, if rotary atomizer is used, air dispersion creates a high degree of rotation, resulting in a uniform drying temperature [
4].
Chitosan nanoparticles preparation was reported in several studies which apply a fundamental of chitosan nanoparticles to the innovative platform for natural molecules or drug delivery [
17,
18,
19] including a cooperation between nano/microparticles formation with spray drying [
20]. Chitosan cross-linking with sodium tripolyphosphate (STPP) are widely used for biomedical and pharmaceutical applications since STPP is classified by the Food and Drug Administration as being a Generally Recognized as Safe Substance (GRAS) [
20].
In the present study, co-processing of chitosan–kaolin via spray drying was aimed at providing superior properties to these compounds compared to the individual excipients or their physical mixture. Chitosan solution converted to chitosan nanoparticles prior to combination with kaolin was found to overcome the drawbacks of the existing chitosan powder in tablet production. The effect of STPP on morphology, flow properties, and tablet hardness of the co-processed excipients were investigated. The functionality of the resulting co-processed chitosan–kaolin as a novel tablet excipient was evaluated, in comparison with commercial co-processed excipients (Avicel SMCC90®).
2. Materials and Methods
2.1. Materials
Chitosan (squid chitosan, product code SQA190) was purchased from Marine Bio Resources Co., Ltd. (Bangkok, Thailand). Kaolin was obtained from Creative Industrial Material Research and Development Center, Lampang city, Thailand. Silicified microcrystalline cellulose; Avicel SMCC90® (product code S71704C, FMC International Company, Little Island, Cork, Ireland) was purchased from Onimax Co., Ltd., Bangkok, Thailand. Sodium tripolyphosphate (CAS No. 7758-29-4, product code 12321JI-057) was a product of Sigma–Aldrich, Darmstadt, Germany. Glacial acetic acid (CAS No. 64-19-7, product code 155220) was a product of QRec chemical, Auckland, New Zealand. All other chemicals used were of analytical reagent grade or equivalent.
2.2. Preparation of Co-Processed Chitosan-Kaolin (CCK) Using the Spray Drying Technique
2.2.1. CCK Preparation
Spray drying of the feed suspension was performed using a Niro rotary atomizer spray dryer (serial no.2648, GEA Niro, Copenhagen, Denmark). The inlet temperature, atomizing air pressure, and feed flow rate were set at 160 °C, 1.2 bar, and 10 mL/min, respectively (from the preliminary study of spray drying parameters). Kaolin was added to chitosan nano/microparticles with constant stirring, and the feed suspension was stirred until the end of spray drying process. The properties of CCK were evaluated including particle morphology, flowability and compression behavior.
2.2.2. Selection of an Optimum Feed Formulation
Chitosan solution of 1%
w/
v concentration was prepared by adding a quantity of chitosan 10 g to 1 L of 2% (
v/v) acetic acid with constant stirring until a complete solution was obtained. Sodium tripolyphosphate was dissolved in water and TPP solution of 1%
w/
v concentration was added dropwise into the chitosan solution under magnetic stirring at room temperature to obtain chitosan nano/microparticles, and then further stirred for 30 min. Kaolin was gradually blended with chitosan nano/microparticles prior to spray drying. The ratios of chitosan/TPP were selected from the preliminary study. Feed formulations for the spray drying process are shown in
Table 1. The effect of the chitosan/kaolin ratio and chitosan/TPP ratio, based on dry chitosan weight, were evaluated with regard to flow properties and particle bonding strength (tablet hardness).
The size of chitosan micro/nanoparticles was observed by particle size analyzer (Zetasizer ZS, Malvern Instruments Ltd., Malvern, UK). Optimum feed formulation providing satisfaction of pharmaceutical excipient properties of CCK was further characterized and compared with Avicel SMCC90®.
2.3. Co-Processed Chitosan-Kaolin (CCK) Characterization
2.3.1. Flow Properties
Flow properties were evaluated via the determination of the angle of repose (AR) and compressibility index (CI) on the freshly spray-dried samples (with a moisture content between 4% and 5%) to minimize the effect of moisture content on flowability. AR was manually measured using the fixed funnel method [
21]. Bulk density is the ratio of weight to the volume of sample. Carefully level the sample powder with constant weight (10 g) into a dry 25 mL graduated cylinder and read the apparent volume to the nearest graduated unit. The cylinder was then mechanically tapped 1250 times using a Jolting volumeter (Stav 2003, Erweka, Langen, Germany) to obtain the tapped volume. Tapped density is determined as the weight of the sample to the volume after tapping a measuring cylinder. An average of three determinations (
n = 3) of all tests was recommended. CI was calculated from the bulk and tapped densities using the equation;
2.3.2. Loss on Drying
The residual moisture of sample in terms of percentage loss on drying (% LOD) was carried out by a moisture balance, Sartorius MA-50 moisture analyzer (Sartorius company, Goettingen, Germany). The co-processed chitosan–kaolin (approximately 1 g) was accurately weighed on to a sample pan and placed in the moisture analyzer. An infrared energy heater was used to heat the sample. The temperature was brought up to 105 °C. As the sample is heated, it loses moisture. The loss of moisture translates to a loss of weight of the sample. When the weight of the sample no longer changes, the instrument shuts off the heat. Moisture is calculated automatically by comparing the initial sample weight to the dried or final sample weight. The test was repeated in triplicate (n = 3).
2.3.3. Tablet Hardness
The sample powder was compressed with an 11.0 mm diameter of a flat-faced punch under the compression pressure of 98 MPa for 10 s, using a hydraulic press machine (C, Carver, Wabash, IN, USA). The average tablet hardness was evaluated for 10 tablets (n = 10).
2.3.4. Scanning Electron Microscopy (SEM)
The shape and surface morphology of co-processed chitosan–kaolin was determined by scanning electron microscopy (JSM-IT300, Joel Ltd., Tokyo, Japan). The sample was sputtered with gold prior to SEM examination.
2.3.5. Powder X-ray Diffraction
The XRD patterns of samples were recorded using powder X-ray diffractometer (D8, Bruker, Bremen, Germany) with a reflection mode (at 40 kV, 40 mA over the range of 5°–80° 2 ϑ using Cu Ka radiation wavelength of 1.5406 Å) to determine the crystalline structure of co-processed chitosan–kaolin, those of the individual excipients, and spray dried chitosan nanoparticles.
2.3.6. Powder Characteristics
Particle size analysis of co-processed chitosan–kaolin was performed using laser diffraction particle size analyzer (Mastersizer S, Malvern Instruments Limited, Worcestershire, UK). Sample was dispersed in ethanol for the measurement. The values of D10, D50, D90, and mean diameter of the particle size distribution were recorded.
Single station automatic gas pycnometer (AccuPyc II 1340, Micromeritics, Norcross, GA, USA) was operated for true density measurement of powders (co-processed chitosan-kaolin, Avicel SMCC90® and physical mixture of chitosan and kaolin). A sample was dried at 60 °C for 24 h before the investigation. True density was calculated using the gas displacement method. Powder was placed in the sample cup, followed by purging with helium gas at 25–30 °C 10 times.
2.4. Evaluation of Co-Processed Excipient Properties
2.4.1. Compression Behavior
Tablet Preparation
A hydraulic press machine and a flat-faced punch (11.0 mm diameter) were used to produce the tablets. The powder was compressed for 10 s at 98, 147, and 196 MPa compression pressure. Each tablet was accurately weighed, with a diameter (mm) and thickness (mm) was determined using a Vernier caliper. The data were recorded to analyze the compression behavior.
Tablet Tensile Strength
A tablet breaking force (PTB-311 Pharmatest, Hainburg, Germany) was used to determine the breaking force of the compacts. The tablet tensile strength can then be calculated using Fell and Newton’s method [
22];
where σ
x is the tensile strength (MPa), X is the hardness (N), d is the diameter of the compact (mm), and t is the thickness of the compact (mm).
2.4.2. Disintegration Property
Tablets of excipients were prepared using a hydraulic press machine at 98 MPa compression pressure. Disintegration test was performed of six tablets (
n = 6) according to the standard USP method [
23] with a disintegration apparatus (Erweka ZT122, Erweka GmbH, Langen, Germany). Disintegration time was recorded when all of the tablets had disintegrated completely.
2.5. Statistical Analysis
All tests were carried out at least in triplicate and expressed as mean ± standard deviation (SD). SPSS (version 17.0, IBM, Chicago, IL, USA) was employed to carry out one-way analysis of variance (ANOVA). Statistical significance between the factor in respond to physical property of co-processed excipient was performed using Tukey’s honestly significant difference (HSD) multiple range test at a 95% confidence level.
4. Conclusions
The successful development of co-processed chitosan–kaolin as a novel tablet excipient was obtained from a feed formulation composed of 55% chitosan and 45% kaolin at the optimum chitosan/TPP ratio of 20:1. Kaolin was prepared as a hydrated material which was allowed to swell in water before being added to chitosan nanoparticles. The homogeneous distribution of chitosan nanoparticles into the hydrated kaolin structure in the feed suspension led to enhance flowability of co-processed chitosan–kaolin and provided the optimum tablet hardness, along with rapid disintegration. Although the CCK-R7 characteristics were not be comparable with those of Avicel SMCC90®, the physical properties and tablet performances were improved compared to the physical mixture of the individual materials.
Based on the results of this study, it may be concluded that it is possible to improve the compressibility and flowability of chitosan and kaolin by the co-processing method while maintaining the good properties of the original chitosan material required for a multifunctional tablet excipient that could be applied in direct compression.
Although the developed CCK-R7 presented the good appearances and physical characteristics, critical parameters should be further carefully evaluated in future development including the adjustment of spray drying for scale-up production, and the tableting behavior in simulated industrial compression conditions. In addition, particle engineering is promising direction and should be further encouraged for pharmaceutical excipient development.