Abstract
Gelatin, commonly used for capsule shells, is mostly imported from Europe and America to Indonesia. However, Indonesia’s rich biodiversity offers abundant natural alternatives like arrowroot and alginate. The need for local raw material independence in pharmaceuticals drives this research. This study aims to determine whether arrowroot starch and sodium alginate with calcium chloride as a crosslinker can replace gelatin capsule shells. This study involved five capsule shell formulas (F1-F5), with evaluations on characteristics, swelling %, disintegration time, dispersive X-ray, Fourier-transform infrared (FTIR) analysis, and simplex lattice design (SLD) method optimization, using commercial capsules (CCs) as a control. We used the one-sample t-test. F3 showed the best results in weight uniformity (0.22 ± 0.01 g), %swelling (45.84 ± 0.08%), and disintegration time (8.22 ± 0.85 min), compared to the CC, i.e., weight uniformity (0.12 ± 0.003 g), %swelling (43.26 ± 0.03%), and disintegration time (6.19 ± 1.38 min). Morphologically, F3 was the most homogeneous, resembling CC. FTIR analysis showed hydroxyl band from carboxylic group shifts indicating crosslinking, with notable changes from 1416.6 to 1386.9/cm in F3 and 1417.7–1394.0/cm in F5 after CaCl₂ addition. SLD validation was performed on three model-generated equations using experimental data. The differences between predicted and experimental results were 34.54% (weight uniformity), 3.12% (swelling), and 5.35% (disintegration time). A one-sample t-test showed no significant differences (α > 0.05). Arrowroot starch and sodium alginate with calcium chloride crosslinker can be used as an alternative to capsule shells.
Keywords: Arrowroot starch, calcium chloride, capsule shell, crosslink, sodium alginate
INTRODUCTION
Generally hard of soft capsules shell made from gelatin, which consist of drug and can be dissolved.[1] Gelatin is a heterogeneous mixture of polypeptides obtained through the hydrolysis of collagen from animal connective tissue.[2]
Indonesia is importing gelatin from Europe and America.[3] Gelatine Manufacturers of Europe reported that in 2018, nearly 80% of gelatin was made from pig skin, 15% from cow skin, and 5% from cow, fish, and pig bones.[4] Porcine gelatin is preferred due to its stability, lower production cost, less waste, and faster pretreatment time compared to bovine gelatin.[5] The use of pig-derived gelatin poses a problem for Indonesian Muslims, as they are prohibited from consuming products with pig ingredients or those made from animals not slaughtered according to Islamic law.[6]
Researchers have begun to research sources of raw materials that are hygienic and acceptable to Muslims.[7] Gelatin alternatives can be sourced from fish and poultry, but their production volume is low, necessitating substitutes from nonanimal polysaccharides.[8]
Polysaccharide materials that can be used as gelatin alternatives include starch and alginate.[9] Alginate is a polysaccharide extracted from brown algae (e.g., Macrocystis pyrifera, Laminaria, and Sargassum) using a weak base. It is nontoxic, nonallergenic, biodegradable, and biocompatible. Since alginic acid is water insoluble, sodium alginate is commonly used in industry.[10]
Starch is a glucose homopolymer with α-glycosidic bonds, consisting of amylopectin and amylose. Amylopectin’s granular properties and strong binding power make it a potential gelatin capsule substitute. Starch is abundant in plant fruits, leaves, stems, roots, and tubers.[11] Arrowroot tubers in Indonesia are a potential starch source, with yields ranging from 1.92 to 2.56 t/ha.[12] Arrowroot tubers contain 98.74% starch, consisting of 24.64% amylose and 73.46% amylopectin.[13]
A crosslinker, CaCl2, was used to optimize the combination of arrowroot starch and alginate. Ca²⁺ ions are nontoxic and safe for capsule shell preparation. Previous studies show that increasing CaCl2 enhances encapsulation efficiency by reducing capsule porosity, helping active substances dissolve in the stomach. Crosslinkers minimize water swelling and increase membrane stability, while also reducing flexibility and increasing rigidity by affecting polymer chain density.[14]
MATERIALS AND METHODS
Materials
The materials used in this research were food-grade arrowroot starch collected from local market, synthesis-grade sodium alginate (Sigma), glycerin (Merck), CaCl2 (Merck), and distilled water.
Methods
Capsule shells preparation
Capsule shell preparation involved weighing the materials according to the formula in Table 1. Arrowroot starch and sodium alginate were dissolved in 50 mL of distilled water, followed by the addition of 1 mL glycerin and 2 mL of 2% CaCl2 solution, based on preliminary study results. F1-F3 were used to determine the optimal amount of CaCl2, with 2 mL proving most effective, which was also used for F4 and F5. The mixture was covered with aluminum foil, heated at 75°C for 1 h with stirring every 30 min. The molded was covered using plastic wrap. Then the capsule shell mixture was spread on the molding and allowed to dry at room temperature for 24–48 h. After drying, the shell was removed from the mold, trimmed, and assembled.
Table 1.
Formula design of capsule shells
| Formula | Arrowroot starch (g) | Sodium alginate (g) | Glycerin (mL) | 2% of CaCl2 (mL) | Distilled water (mL) |
|---|---|---|---|---|---|
| F1 | 5 | 5 | 1 | 1 | 50 |
| F2 | 5 | 5 | 1 | 1.5 | 50 |
| F3 | 5 | 5 | 1 | 2 | 50 |
| F4 | 10 | 0 | 1 | 2 | 50 |
| F5 | 0 | 10 | 1 | 2 | 50 |
Capsule shells evaluation
Weight was measured with an analytical balance, and length and diameter with calipers. Disintegration time was tested using a disintegration tester. Swelling ability was evaluated by weighing the dry (W dry) and wet (W wet) shells, with the wet shell obtained by immersing it in distilled water for 10–15 s. %swelling was calculated using the Equation 1 as follows.[15]
The capsule shell’s morphology and elemental content were analyzed using Scanning Electron Microscopy with Energy Dispersive X-Ray analysis (SEM_EDX) by cutting the shell into 1 cm × 1 cm pieces. Crosslinking was examined through Fourier-transform infrared (FTIR) by crushing the shell and compacted using KBr, then analyzing its functional groups.[16] The optimal formula was evaluated with SLD, and its validity was confirmed by comparing predicted and experimental data using a one-sample t-test.
RESULTS AND DISCUSSION
Capsule shell preparation
Starch and alginate are the main ingredients in capsule shells. Starch, consisting of 73.46% amylopectin (insoluble) and 24.64% amylose (soluble), forms capsule shells through gelatinization. When amylose dissolves in water at 70°C–80°C, it thickens due to gelatinization.[17] Amylose’s swelling and binding properties make it a potential gelatin substitute for capsule shells. Sodium alginate enhances physical and mechanical properties when combined with starches, and is nontoxic, biocompatible, biodegradable, affordable, and forms gels via calcium ion chelation with L-guluronate chains. Polysaccharide-based capsule shells are fragile, so glycerin is added as a plasticizer to reduce brittleness and improve elasticity.[18] Glycerin, a hydrophilic plasticizer, has binding ability.[8] The starch-alginate capsule shells are thin, porous, and have low mechanical strength. To optimize them, CaCl2 was added as a crosslinker, reducing water swelling and increasing stability. Crosslinking also increases polymer chain density, reducing flexibility and adding stiffness. CaCl2 was chosen for its low toxicity and water-soluble properties.[19] The characteristics of capsule shell made by this research are presented in Figure 1.
Figure 1.
Characteristics of capsule shells. F1: plastic, strong, smooth (a); F2: plastic, strong, smooth (b); F3: plastic, strong, smooth (c); F4: rigid, strong, smooth (d); and F5: plastic, strong, rough (e)
Capsule shell evaluation
Capsule shell specifications
The measured diameter and weight of capsule shells did not comply with standard specifications. These differences may result from factors like variations in raw materials, the arrowroot starch-to-alginate ratio, and the manual manufacturing process, which can cause uneven capsule shell thickness. Commercial capsules (CCs) were used as a control in this study. The capsule shell specification is presented in Table 2.
Table 2.
Capsule shell specification compared with commercial capsule
| Formula | Long (mm) |
Diameter (mm) |
Weight (g) | |||
|---|---|---|---|---|---|---|
| Body | Cap | Body + cap | Body | Cap | ||
| F1 | 19.97±3.57 | 12.35±2.21 | 23.73±4.24 | 8.12±1.45 | 8.50±1.52 | 0.28±0.05 |
| F2 | 19.83±2.85 | 12.32±1.76 | 23.70±3.39 | 8.15±1.12 | 8.53±1.18 | 0.29±0.04 |
| F3 | 20.18±0,71 | 12.33±0.04 | 23.80±0.85 | 8.12±0.37 | 8.42±0.38 | 0.22±0.01 |
| F4 | 19.80±2.14 | 12.03±1.32 | 23.93±2.54 | 9.12±0.61 | 9.52±0.63 | 0.45±0.03 |
| F5 | 19.73±2.14 | 12.07±1.32 | 23.78±1.43 | 8.13±0.49 | 8.53±0.51 | 0.50±0.03 |
| Commercial capsule (CC) | 19.50-20.50 | 11.50-12.50 | 23.30-24.45 | 8.16±0.10 | 8.50±0.10 | 0.13±0.003 |
%swelling
Swelling degree can be adjusted for specific uses, such as easily breaking capsules for ulcer medicine or more resistant ones for intestinal use. F3 had the closest results to CC at 45.84 ± 0.08% [Table 3].
Table 3.
% swelling of capsule shell compared with commercial capsule
| Formula | Average of disintegration time (min) |
|---|---|
| F1 | 47.17±0.08 |
| F2 | 54.15±0.06 |
| F2 | 45.84±0.08 |
| F4 | 12.11±0.03 |
| F5 | 55.05±0.08 |
| CC | 42.60±0.03 |
Disintegration time
F4 did not meet the disintegration time standard compared to CC, as thicker capsules require more time to disintegrate.[20] Using 100% arrowroot starch can prolong disintegration time, as it contains hydrophilic amylose (24.64%) and hydrophobic amylopectin (73.46%).[21] Amylopectin in F4 causes a longer disintegration time. The F3’s disintegration time, 8.22 ± 0.85 min, was closest to CC [Table 4].
Table 4.
Disintegration time of capsule shell compared with commercial capsule
| Formula | Average of disintegration time (min) |
|---|---|
| F1 | 7.93±0.72 |
| F2 | 8.12±0.79 |
| F2 | 8.22±0.85 |
| F4 | 43.08±6.84 |
| F5 | 11.09±1.89 |
| CC | 6.19±1.39 |
Dispersive X-ray (SEM-EDX)
SEM analysis at ×750 magnification [Figure 2a] showed that F4 (100% arrowroot starch) and F5 (100% sodium alginate) had uneven, inhomogeneous surfaces. In contrast, F3 (50:50 starch–alginate) displayed a more uniform structure, resembling the CC. This improved morphology may result from crosslinking between arrowroot starch, sodium alginate, and CaCl₂.
Figure 2.
Morphology of the capsule shell surface at ×750 magnification (a). Elemental content of capsule shell (b)
EDX analysis of the capsule shells [Figure 2b] showed the presence of calcium (Ca) as a crosslinker in all formulas. F4, made from 100% arrowroot starch (87.68% carbohydrate (Cn (H2O) n)), was dominated by carbon (60.34%) and oxygen (29.29%).[22] Calcium was present at 2.80% in F4. EDX analysis of F3 revealed a shell dominated by C (54.77%), O (33.17%), and Na (9.02%), consistent with its 50:50 composition of arrowroot starch (87.68% carbohydrate) and sodium alginate ([C₆H₇O₆Na]ₙ), containing 0.45% calcium. EDX analysis of F5 showed a shell dominated by C (42.59%), O (40.42%), Ca (3.24%), and Na (8.78%), consistent with its 100% sodium alginate composition. In contrast, CCs were dominated by C (48.05%), O (31.87%), and N (18.53%), with 0.83% Ca. The high nitrogen content in the CC reflects its gelatin-based, protein-derived composition.
Fourier-transform infrared analysis (FTIR analysis)
The FTIR spectra of polysaccharides commonly generate some peaks as follows. A broad O–H band at ~3300/cm, indicating strong hydrogen bonding in polysaccharides. Peaks at ~1600 and ~1400/cm confirm carboxylate groups. C–O and C–O–C vibrations represent the polysaccharide backbone, and the ~950/cm peak relates to the epimeric structure of M and G blocks in alginate. FTIR analysis [Figure 3] identifies the functional groups in all formula’s capsule shells, summarized in Table 5. Hydroxyl groups (O-H bending) from carboxylate groups present in F3 and F5, with and without CaCl₂. In the 50% starch and 50% alginate shell, the O-H band from carboxylate groups shifted from 1416.6/cm (without CaCl₂) to 1386.9/cm (with CaCl₂). Similarly, in the 100% alginate shell, the band shifted from 1417.7/cm to 1394.0/cm with CaCl₂, indicating crosslinking and structural flexibility.[23,24] This proves that there is a new link between capsule shell material with the CaCl2 crosslinker, which is identified from the shifting of the functional group. The bond that may occur hypothesizes that Ca2+ is from the crosslinker CaCl2. It will bind to the hydroxyl groups on the carboxylic acid groups of the alginate’s G-G (guluronate-guluronate) block.[25]
Figure 3.
Infrared spectra of capsule shells. F3 (a); F4 (b); and F5 (c)
Table 5.
Functional groups from IR spectra identification on capsule shells
| Analysis results | Wave number (cm-1)a | Wave number (cm-1)b | |||
|---|---|---|---|---|---|
|
| |||||
| F3 | F4 | F5 | F4 | F5 | |
| C-X (X=halogen) | 547.54-684.40 | 542.32 | 554.82-617.97 | ||
| C-C-C, C-C-O and C-O-C Cyclic alkane skeletal breathing, O-H out-of-plane banding 3000-4000 O-H stretching (forming intermolecular forces) |
614-800 | 612-800 | |||
| C=C bending | 803.22 | ||||
| N/A | 822.37 | ||||
| C-O, C-N, C-C stretching | 994.26 | 1108.98 | 1105.60 | ||
| C-O stretching from ether, secondary alcohols | 1023-1155 | 1058-1111 | |||
| C-O, C-N, C-C stretching | 1110.18 | 1259.00 | 1258.06 | ||
| C-O stretching from ether | 1262.3 | 1263.8 | |||
| O-H bending from alcohols | 1327.7 | 1327.0 | |||
| CH2 wagging band progression, O-H bending | 1386.90 | 1394.00 | |||
| O-H bending from carboxylic acid groups | 1416.6 | 1417.7 | |||
| C-H bending from alkanes | 1462.54 | 1488.25 | |||
| -OH from adsorbed water | 1604.7 | 1604 | |||
| C=O stretching | 1622.23 | 1672.68 | 1630.13 | ||
| C≡N, Si-H | 2350.71 | 2085.50 | |||
| 2476.86 | 2144.48 | ||||
| 2536.43 | 2351.48 | ||||
| S-H stretching | 2584.76 | 2540.07 | |||
| C-H stretching | 2673.04 | 2687.89 | |||
| Symmetric C-H stretching | 2855.04 | 2857.86 | |||
| Asymmetric C-H stretching | 2924.12 | 2922.20 | 2937.25 | ||
| C-H stretching from alkanes | 2926 | 2924.4 | |||
| O-H stretching (forming intermolecular forces) | 3000-4000 | ||||
| O-CH3, C-H stretching | 3033.67 | 3063.74 | 3063.74 | ||
| 3080.11 | |||||
| N-H stretching (non-hydrogen bonded) | 3431.99 | 3446.20 | 3437.05 | ||
| N-H stretching, C-H stretching | 3704.73 | 3703.60 | |||
| O-H and N-H stretching, C-H stretching | 3784.02 | ||||
a: with CaCl2 crosslinker; b: without CaCl2 crosslinker
Optimization with SLD method
The SLD method predicts the optimal capsule formula to achieve desired characteristics, including weight uniformity, %swelling, and disintegration time. The evaluation parameters are expressed in equations for weight uniformity (Equation 2), %swelling (Equation 3), and disintegration time (Equation 4), where Y is the response, A is arrowroot starch amount, and B is sodium alginate amount:
Then, each parameter was weighted using the ratio of weight uniformity (%SD): %swelling: disintegration time (0.3: 0.3: 0.4). The disintegration time is more influential than other parameters. The relationship between the calculation results of the SLD method with the composition of arrowroot starch and sodium alginate can be shown in Figure 4. Figure 4 shows that increasing alginate reduced weight uniformity [Figure 4a], increased %swelling up to a peak at 10% starch and 90% alginate [Figure 4b], and accelerated disintegration time up to 30% starch and 70% alginate before slowing again [Figure 4c]. The SLD equation identifies the optimal formula range by maximizing the total response through normalization [Table 6].
Figure 4.
Relationship between weight uniformity (%SD) with arrowroot starch and sodium alginate (a); %swelling with arrowroot starch and sodium alginate (b); and disintegration time with arrowroot starch and sodium alginate (c)
Table 6.
Total response of capsule shells
| Arrowroot starch: sodium alginate | Weight uniformity (% SD) | % swelling | Disintegration time | Response total |
|---|---|---|---|---|
| 100: 0 | 0.300 | 0.000 | 0.396 | 0.696 |
| 90: 10 | 0.261 | 0.062 | 0.293 | 0.615 |
| 80: 20 | 0.223 | 0.115 | 0.205 | 0.543 |
| 70: 30 | 0.187 | 0.162 | 0.133 | 0.481 |
| 60: 40 | 0.152 | 0.202 | 0.076 | 0.430 |
| 50: 50 | 0.118 | 0.235 | 0.035 | 0.389 |
| 40: 60 | 0.087 | 0.261 | 0.010 | 0.358 |
| 30: 70 | 0.056 | 0.281 | 0.000 | 0.337 |
| 20: 80 | 0.027 | 0.294 | 0.006 | 0.327 |
| 10: 90 | 0.000 | 0.300 | 0.027 | 0.327 |
| 0: 100 | 0.002 | 0.299 | 0.065 | 0.366 |
Based on the total response value, the most optimum formula is F4, because it has the highest total response value of 0.696. The more alginate added, the greater the %swelling and the faster the disintegration time of the capsule shells; however, the smaller the weight uniformity (%SD).
Validation test
The validation test ensured that the SLD method accurately predicted capsule shell formulations using arrowroot starch and sodium alginate. A predicted formula with a 60:40 starch-to-alginate ratio was randomly selected and prepared to compare its actual response with the expected result. Figure 5 illustrates the predicted versus experimental data for weight uniformity [Figure 5a], swelling [Figure 5b], and disintegration time [Figure 5c]. The differences were calculated using Equation 5:
Figure 5.
Comparison between prediction formula and experimental results. The capsule shells evaluations are weight uniformity (%SD) (a); %swelling (b); and disintegration time (c)
The difference between weight uniformity (%SD), %swelling, and disintegration time of prediction and experimental data of capsule shells were 34.54%; 3.12%; and 5.35%, respectively. The prediction data with the experimental results were also subjected to statistical analysis with a one-sample t-test. The one-sample t-test aims to test that the predicted value with the SLD method is significantly different from the average value of the experimental results. In the normality test using the Shapiro–Wilk test, %swelling and disintegration time of capsule shells, all data were normally distributed with values of 0.173 and 0.674, respectively (α > 0.05). Meanwhile, in the one-sample t-test, all predicted data were not significantly different from the experimental data (α > 0.05), where the % swelling and disintegration time values were 0.579 and 0.581, respectively.
CONCLUSION
Based on the results of capsule shells evaluations, F3 has the best characteristics compared to other formulas. F3 and F5 with calcium chloride also experienced flexibility on hydroxyl groups, as seen from the IR spectra. In the optimization results with the SLD method, F4 has the highest total response value compared to other formulas. Therefore, arrowroot starch and sodium alginate with calcium chloride crosslinker have the potential for further development as an alternative to gelatin capsule shells.
Conflicts of interest
There are no conflicts of interest.
Acknowledgment
The research grant from Ministry of Education, Culture, Research, and Technology of Indonesia under the DRTPM Regular Fundamental research scheme with contract number 0459/E5/PG.02.00/2024 dated May 30, 2024 to the authors are highly acknowledged.
Funding Statement
The Ministry of Education, Culture, Research and Technology of the Republic of Indonesia under the DRTPM regular fundamental research scheme with research contract number 0459/E5/PG.02.00/2024 dated May 30, 2024
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